Substituted bicyclic derivatives useful as anticancer agents

ABSTRACT

The invention relates to compounds of the formula 1  
                 
 
     and to pharmaceutically acceptable salts and solvates thereof, wherein A, X, R 1 , R 3  and R 4  are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals with administering the compounds of formula 1 and to pharmaceutical compositions for treating such disorders which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.

BACKGROUND OF THE INVENTION

[0001] This invention relates to novel bicyclic derivatives that areuseful in the treatment of abnormal cell growth, such as cancer, inmammals. This invention also relates to a method of using such compoundsin the treatment of abnormal cell growth in mammals, especially humans,and to pharmaceutical compositions containing such compounds.

[0002] It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e., a genewhich, on activation, leads to the formation of malignant tumor cells).Many oncogenes encode proteins that are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

[0003] Receptor tyrosine kinases are enzymes which span the cellmembrane and possess an extracellular binding domain for growth factorssuch as epidermal growth factor, a transmembrane domain, and anintracellular portion which functions as a kinase to phosphorylatespecific tyrosine residues in proteins and hence to influence cellproliferation. Other receptor tyrosine kinases include c-erbB-2, c-met,tie-2, PDGFr, FGFr, and VEGFR. It is known that such kinases arefrequently aberrantly expressed in common human cancers such as breastcancer, gastrointestinal cancer such as colon, rectal or stomach cancer,leukemia, and ovarian, bronchial or pancreatic cancer. It has also beenshown that epidermal growth factor receptor (EGFR), which possessestyrosine kinase activity, is mutated and/or overexpressed in many humancancers such as brain, lung, squamous cell, bladder, gastric, breast,head and neck, oesophageal, gynecological and thyroid tumors.

[0004] Accordingly, it has been recognized that inhibitors of receptortyrosine kinases are useful as selective inhibitors of the growth ofmammalian cancer cells. For example, erbstatin, a tyrosine kinaseinhibitor, selectively attenuates the growth in athymic nude mice of atransplanted human mammary carcinoma which expresses epidermal growthfactor receptor tyrosine kinase (EGFR) but is without effect on thegrowth of another carcinoma which does not express the EGF receptor.Thus, the compounds of the present invention, which are selectiveinhibitors of certain receptor tyrosine kinases, are useful in thetreatment of abnormal cell growth, in particular cancer, in mammals. Inaddition to receptor tyrosine kianses, the compounds of the presentinvention can also display inhibitory activity against a variety ofother non-receptor tyrosine kinases (eg: Ick, src, abl) orserine/threonine kinases (e.g.: cyclin dependent kinases).

[0005] Various other compounds, such as styrene derivatives, have alsobeen shown to possess tyrosine kinase inhibitory properties. Morerecently, five European patent publications, namely EP 0 566 226 A1(published Oct. 20, 1993), EP 0 602 851 A1 (published Jun. 22, 1994), EP0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1 (published Jan.25, 1995), and EP 0 520 722 A1 (published Dec. 30, 1992), refer tocertain bicyclic derivatives, in particular quinazoline derivatives, aspossessing anti-cancer properties that result from their tyrosine kinaseinhibitory properties. Also, World Patent Application WO 92/20642(published Nov. 26, 1992), refers to certain bis-mono and bicyclic aryland heteroaryl compounds as tyrosine kinase inhibitors that are usefulin inhibiting abnormal cell proliferation. World Patent ApplicationsWO96/16960 (published Jun. 6, 1996), WO 96/09294 (published Mar. 6,1996), WO 97/30034 (published Aug. 21, 1997), WO 98/02434 (publishedJan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO 98/02438(published Jan. 22, 1998), also refer to substituted bicyclicheteroaromatic derivatives as tyrosine kinase inhibitors that are usefulfor the same purpose.

SUMMARY OF THE INVENTION

[0006] The present invention relates to compounds of the formula 1

[0007] and to pharmaceutically acceptable salts and solvates thereof,wherein:

[0008] X is N or CH;

[0009] A represents a fused 5, 6 or 7-membered ring optionallycontaining 1 to 4 heteroatoms which may be the same or different andwhich are selected from —N(R¹)—, O, and S(O)_(j), wherein j is aninteger from 0 to 2, the fused ring containing a total of 1, 2 or 3double bonds inclusive of the bond in the pyridine or pyrimidine ring towhich it is fused wherein the R¹ group attached to the nitrogen isabsent if a double bond includes the foregoing optional nitrogen moiety—N(R¹)—, with the proviso that the fused ring does not form part of apurine and that the fused ring does not contain two adjacent O orS(O)_(j) atoms, and wherein the carbon atoms of the A moiety areoptionally substituted with 1 to 3 R⁵ groups;

[0010] each R¹ and R² is independently H or C₁-C₆ alkyl;

[0011] R³ is —(CR¹R²)_(m)—R⁸ wherein m is 0 or 1;

[0012] or R¹ and R³ are taken together to form a group of the formula

[0013] wherein said group is optionally substituted with 1 to 3 R⁵groups;

[0014] R⁴ is —(CR¹R²)_(m)—C≡C—(CR¹R²),R⁹, —(CR¹R²)_(m)—C═C—(CR¹R²), —R⁹,—C═NOR¹², or —X¹—R¹² wherein m is an integer from 0 to 3, t is aninteger from 0 to 5, and X¹ is a divalent group derived from azetidine,oxetane or a C₃-C₄ carbocyclic group;

[0015] or R⁴ is —(CR¹R²)_(m)—C≡C—(CR¹R²)_(k)R¹³ or—(CR¹R²)_(m)—C═C—(CR¹R²)_(k)R¹³ wherein k is an integer from 1 to 3 andm is an integer from 0 to 3;

[0016] or R⁴ is —(CR¹R²)R⁹, wherein t is an integer from 0 to 5 and theattachment point to R⁹ is through a carbon atom of the R⁹ group;

[0017] each R⁵ is independently selected from halo, hydroxy, —NR¹R²,C₁-C₆ alkyl, trifluoromethyl, C₁-C₆ alkoxy, trifluoromethoxy, —C(O)R⁶,—CO₂R⁶, —NR⁶C(O)R1, —C(O)NR⁶R⁷, —SO₂NR⁶R⁷, —NR⁶C(O)NR⁷R¹, and—NR⁶C(O)OR⁷;

[0018] each R⁶ and R⁷ is independently selected from H, C₁-C₆ alkyl,—(CR¹R²)_(t)(C₆-C₁₀ aryl), and —(CR¹R²),(4-10 membered heterocyclic),wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of theheterocyclic group are optionally substituted with an oxo (═O) moiety,and the alkyl, aryl and heterocyclic moieties of the foregoing R⁶ and R⁷groups are optionally substituted with 1 to 3 substituents independentlyselected from halo, cyano, nitro, —NR¹R², trifluoromethyl,trifluoromethoxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxy,and C₁-C₆ alkoxy;

[0019] R⁸ is independently selected from —(CR¹R²)_(t)(C₆-C₁₀ aryl) and—(CR¹R²)_(t)(4-10 membered heterocyclic), wherein t is an integer from 0to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionallysubstituted with an oxo (═O) moiety, and each of the foregoing R⁸ groupsis optionally substituted with 1 to 5 R¹⁰ groups;

[0020] R⁹ is a non-aromatic mono-cyclic ring, a fused or bridgedbicyclic ring, or a spirocyclic ring, wherein said ring contains from 3to 12 carbon atoms in which from 0 to 3 carbon atoms are optionallyreplaced with a hetero moiety independently selected from N, O, S(O)_(j)wherein is an integer from 0 to 2, and —NR²—, provided that two O atoms,two S(O)_(j) moieties, an O atom and a S(O)_(j) moiety, an N atom and anS atom, or an N atom and an O atom are not attached directly to eachother within said ring, and wherein the carbon atoms of said ring areoptionally substituted with 1 to 2 R¹¹ groups;

[0021] each R¹⁰ is independently selected from halo, cyano, nitro,trifluoromethoxy, trifluoromethyl, azido, hydroxy, C₁-C₆ alkoxy, C₁-C₁₀alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,—NR⁶C(O)R⁷, —NR⁶C(O)NR¹R⁷, —NR⁶C(O)OR⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷,—SO₂NR⁶R⁷, —S(O)_(j)(C₁-C₆ alkyl) wherein j is an integer from 0 to 2,—(CR¹R²)_(t)(C₆-C₁₀ aryl), —(CR¹R²)_(t)(4-10 membered heterocyclic),—(CR¹R²)_(q)C(O)(CR¹R²),(C₆-C₁₀ aryl), —(CR¹R²)_(q)C(O)(CR¹R²)_(t)(4-10membered heterocyclic), —(CR¹R²)_(t)O(CR¹R²)_(q)(C₆-C₁₀aryl),—(CR¹R²)_(t)O(CR¹R²)_(q)(4-10 membered heterocyclic),—(CR¹R²)_(q)S(O)_(j)(CR¹R²)_(t)(C₆-C₁₀ aryl), and—(CR¹R²)_(q)S(O)_(j)(CR¹R²)_(t)(4-10 membered heterocyclic), wherein jis 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R¹⁰groups are optionally substituted with an oxo (═O) moiety, and thealkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoingR¹⁰ groups are optionally substituted with 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl,trifluoromethoxy, azido, —OR⁶, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷,—C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—(CR¹R²),(C₆-C₁₀aryl), and —(CR¹R²)_(t)(4-10 membered heterocyclic),wherein t is an integer from 0 to 5;

[0022] each R¹¹ is independently selected from —R¹², —OR¹, —NR¹R²,—NR⁶C(O)R⁷, —NR⁶C(O)NR⁷R¹, —NR⁶C(O)OR⁷, and —NR⁶SO₂NR⁷R¹, or R¹¹replaces two hydrogen atoms on a carbon to form an oxo (C═O) group;

[0023] R¹² is R⁶, —C(O)R⁶ or —SO₂R⁶, —C(O)NR⁶R⁷, —SO₂NR⁶R⁷, or —CO₂R⁶;

[0024] R¹³ is —NR¹R¹² or —OR¹²;

[0025] and wherein any of the above-mentioned substituents comprising aCH₃ (methyl), CH₂ (methylene), or CH (methine) group which is notattached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said group a substituent selected from hydroxy,halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and —NR¹R².

[0026] In a specific embodiment of the present invention, the A moietyof the compounds of formula 1 is selected from

[0027] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0028] Other specific embodiments of the compounds of formula 1 includethose wherein A is selected from

[0029] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0030] Other specific embodiments of the compounds of formula 1 includethose wherein A is selected from

[0031] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0032] Other specific embodiments of the compounds of formula 1 includethose wherein A is selected from

[0033] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0034] Other specific embodiments of the compounds of formula 1 includethose wherein A is

[0035] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0036] Other specific embodiments of the compounds of formula 1 includethose wherein R⁴ is —(CR¹R²)_(m)—C≡C—(CR¹R²)_(t)R⁹ wherein m is aninteger from 0-3 and t is an integer from 0-5.

[0037] Other specific embodiments of the compounds of formula 1 includethose wherein R⁴ is —(CR¹R²)_(m)—C═C—(CR¹R²)_(t)—R⁹ and m is an integerfrom 0 to 3 and t is an integer from 0-5.

[0038] Other specific embodiments of the compounds of formula I includethose wherein R⁴—(CR¹R²)_(m)—C≡C—(CR¹R²)_(k)R¹³ or—(CR¹R²)_(m)—C═C—(CR¹R²)_(k)R¹³ wherein m is an integer from 0-3 and kis an integer from 1 to 3

[0039] Other specific embodiments of the compounds of formula I includethose wherein R⁴ is is —C═NOR¹², or —X¹—R¹² wherein X¹ is a divalentgroup derived from azetidine, oxetane or a C₃-C₄ carbocyclic group; orR⁴ is —(CR¹R²)_(t)R⁹, wherein the attachment point to R⁹ is through acarbon atom of R⁹.

[0040] Other specific embodiments of the compounds of formula 1 includethose wherein R⁸ is selected from —(CR¹R²)_(t)(phenyl),—(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²)_(t)(benzimidazolyl), wherein t isan integer from 0 to 5, and each of the foregoing R⁸ groups isoptionally substituted with 1 to 5 R¹⁰ groups.

[0041] Other specific embodiments of the compounds of formula 1 includethose wherein R⁹ is a 4 to 10 membered heterocyclic group having 1 to 3hetero moieties as indicated in formula 1 above and wherein said R⁹ isoptionally substituted with 1 to 2 R¹⁰ groups.

[0042] Preferred compounds include those selected from the groupconsisting of:

[0043] Acetic acid3-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-allylester;

[0044](1-Benzenesulfonyl-1H-indol-5-yl)-{6-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-quinazolin-4-yl}-amine;

[0045](1-Benzenesulfonyl-1H-indol-5-yl)-[6-(3-pyrrolidin-1-yl-prop-1-ynyl)-quinazolin-4-yl]-amine;

[0046]4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol;

[0047](1-Benzenesulfonyl-1H-indol-5-yl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;

[0048][6-(4-Amino-tetrahydro-pyran-4-ylethynyl)-quinazolin-4-yl]-(1-benzenesulfonyl-1H-indol-5-yl)-amine;

[0049]1-Methyl-4-{4-[3-methyl-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylethynyl}-piperidin-4-ol;

[0050]1-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol;

[0051]4-{4-[4-(1-Phenyl-ethoxy)-phenylamino]-quinazolin-6-ylethynyl-tetrahydro-pyran-4-ol;

[0052]1-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-4,4-dimethyl-pent-1-yn-3-ol;

[0053]4,4-Dimethyl-1-{4-[4-(1-phenyl-ethoxy)-phenylamino]-quinazolin-6-yl}-pent-1-yn-3-ol;

[0054]3-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;

[0055]1-Methyl-3-[4-(4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0056]3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0057]3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-pyrrolidin-2-yl-prop-2-yn-1-ol;

[0058]5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-ylethynyl]-4,4-dimethyl-oxazolidin-2-one;

[0059]4-Amino-1-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol;

[0060]4-Amino-1-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol;

[0061]3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol;

[0062] and the pharmaceutically acceptable salts and solvates of theforegoing compounds.

[0063] In accordance with the present invention, the most preferredcompounds include those selected from the group consisting of:

[0064](+)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(R)-ylethynyl-quinazolin-4-yl)-amine;

[0065](−)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(S)-ylethynyl-quinazolin-4-yl)-amine;

[0066]3-(S)-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylicacid methylamide;

[0067]3-(S)-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylicacid methylamide;

[0068](3-Methyl-4-phenoxy-phenyl)-(6-pyrrolidin-3-ylethynyl-quinazolin-4-yl)-amine;

[0069]3-[4-(5-Methyl-6-phenoxy-pyridin-3-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0070](−)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0071](+)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0072]4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-4-ol;

[0073]{6-[11-(2-Methoxy-ethyl)-piperidin-3-ylethynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;

[0074][4-(2-Fluoro-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;

[0075][4-(3-Fluoro-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;

[0076](6-Azetidin-3-ylethynyl-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine;

[0077]3-{4-[4-(2-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;

[0078]3-{4-[4-(3-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;

[0079]4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol;

[0080](3-Chloro-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;

[0081]3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1]octan-3-ol;

[0082] (3-Chloro-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;

[0083]3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-3-ol;

[0084] 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-7-ylethynyl]-piperidin-3-ol;

[0085] and the pharmaceutically acceptable salts and solvates of theforegoing compounds.

[0086] Other preferred compounds include those selected from the groupconsisting of:

[0087] N-{3-[4-(3-Chloro4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;

[0088] N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;

[0089](3-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0090]4-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazine-1-carboxylicacid methylamide;

[0091]{6-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)-prop-1-ynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;

[0092] 1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-4-ol;

[0093] N-{1-Methyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazol in-6-yl]-prop-2-ynyl}-acetamide;

[0094]N-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-methyl-prop-2-ynyl}-acetamide;

[0095]N-{1,1-Dimethyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;

[0096]4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-1-methyl-piperidin-4-ol;

[0097]3-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0098]3-[4-(3-Bromo-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0099]3-[4-(4-Benzenesulfonyl-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0100]3-[4-(4-Cyclohexyloxy-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0101]2-Methyl-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-2-ol;

[0102]2-Amino-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-1-ol;

[0103]3-[4-(3-Methyl-4-phenylsulfanyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0104] and the pharmaceutically acceptable salts and solvates of theforegoing compounds.

[0105] Other preferred compounds of the present invention include thoseselected from the group consisting of:

[0106]3-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0107]3-[4-(3-Ethynyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0108](3-Methyl-4-phenoxy-phenyl)-[6-(1-methyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-amine;

[0109] (3-Methyl-4-phenoxy-phenyl)-[6-(2-piperidin-3-yl-ethyl)-quinazolin-4-yl]-amine;

[0110]3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol;

[0111]3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;

[0112]3-Oxo-5-(4-pyrrolidin-1-yl-butyl)-1,2,3,5-tetrahydro-benzo[4,5]imidazo[1,2-a]pyridine-4-carboxylicacid benzylamide;

[0113] and the pharmaceutically acceptable salts and solvates of theforegoing compounds.

[0114] This invention also relates to a method for the treatment ofabnormal cell growth in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula 1,as defined above, or a pharmaceutically acceptable salt or solvatethereof, that is effective in treating abnormal cell growth. In oneembodiment of this method, the abnormal cell growth is cancer,including, but not limited to, lung cancer, bone cancer, pancreaticcancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of theforegoing cancers. In another embodiment of said method, said abnormalcell growth is a benign proliferative disease, including, but notlimited to, psoriasis, benign prostatic hypertrophy or restinosis.

[0115] This invention also relates to a method for the treatment ofabnormal cell growth in a mammal which comprises administering to saidmammal an amount of a compound of formula 1, or a pharmaceuticallyacceptable salt or solvate thereof, that is effective in treatingabnormal cell growth in combination with an anti-tumor agent selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

[0116] This invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt or solvate thereof, that iseffective in treating abnormal cell growth, and a pharmaceuticallyacceptable carrier. In one embodiment of said composition, said abnormalcell growth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

[0117] The invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,which comprises an amount of a compound of formula 1, as defined above,or a pharmaceutically acceptable salt or solvate thereof, that iseffective in treating abnormal cell growth in combination with apharmaceutically acceptable carrier and an anti-tumor agent selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, and anti-androgens.

[0118] The invention also relates to a method of preparing a compound ofthe formula 1

[0119] and pharmaceutically acceptable salts and solvates thereof,wherein A, X, R¹, R⁴ and R³ are as defined above, which comprises either(a) reacting a compound of the formula 11 or 2 with a compound of theformula 3

[0120] wherein Z is a leaving group and A, X, R¹, R⁴ and R³ are asdefined above, or (b) reacting a compound of the formula 7 with acompound of the formula 3

[0121] wherein X, R¹, A, R¹ and R³ are as defined above and Z¹ is anactivating group, to provide an intermediate of the formula 5

[0122] wherein Z¹, X, R¹, A, and R³ are as defined above and Z¹ isconverted to an R⁴ group.

[0123] “Abnormal cell growth”, as used herein, unless otherwiseindicated, refers to cell growth that is independent of normalregulatory mechanisms (e.g., loss of contact inhibition). This includesthe abnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; (4) anytumors that proliferate by receptor tyrosine kinases; (5) any tumorsthat proliferate by aberrant serine/threonine kinase activation; and (6)benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs.

[0124] The term “treating”, as used herein, unless otherwise indicated,means reversing, alleviating, inhibiting the progress of, or preventingthe disorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

[0125] The term “halo”, as used herein, unless otherwise indicated,means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro,chloro and bromo.

[0126] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched, or cyclic moieties (including fused and bridged bicyclic andspirocyclic moieties), or a combination of the foregoing moieties. Foran alkyl group to have cyclic moieties, the group must have at leastthree carbon atoms.

[0127] The term “alkenyl”, as used herein, unless otherwise indicated,includes alkyl moieties having at least one carbon-carbon double bondwherein alkyl is as defined above and including E and Z isomers of saidalkenyl moiety.

[0128] The term “alkynyl”, as used herein, unless otherwise indicated,includes alkyl moieties having at least one carbon-carbon triple bondwherein alkyl is as defined above.

[0129] The term “alkoxy”, as used herein, unless otherwise indicated,includes O-alkyl groups wherein alkyl is as defined above.

[0130] The term “aryl”, as used herein, unless otherwise indicated,includes an organic radical derived from an aromatic hydrocarbon byremoval of one hydrogen, such as phenyl or naphthyl.

[0131] The term “4-10 membered heterocyclic”, as used herein, unlessotherwise indicated, includes aromatic and non-aromatic heterocyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4-10 atoms in its ring system,and with the proviso that the ring of said group does not contain twoadjacent O or S atoms. Non-aromatic heterocyclic groups include groupshaving only 4 atoms in their ring system, but aromatic heterocyclicgroups must have at least 5 atoms in their ring system. The heterocyclicgroups include benzo-fused ring systems. An example of a 4 memberedheterocyclic group is azetidinyl (derived from azetidine). An example ofa 5 membered heterocyclic group is thiazolyl and an example of a 10membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Examples ofaromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Theforegoing groups, as derived from the groups listed above, may beC-attached or N-attached where such is possible. For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole may beimidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An example ofa heterocyclic group wherein 2 ring carbon atoms are substituted withoxo (═O) moieties is 1,1-dioxo-thiomorpholinyl.

[0132] The phrase “pharmaceutically acceptable salt(s)”, as used herein,unless otherwise indicated, includes salts of acidic or basic groupswhich may be present in the compounds of formula 1. The compounds offormula 1 that are basic in nature are capable of forming a wide varietyof salts with various inorganic and organic acids. The acids that may beused to prepare pharmaceutically acceptable acid addition salts of suchbasic compounds of formula 1 are those that form non-toxic acid additionsalts, i.e., salts containing pharmacologically acceptable anions, suchas the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate,estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate,laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate,napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate,pantothenate, phospate/diphosphate, polygalacturonate, salicylate,stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodode, and valerate salts. Since a single compound of the presentinvention may include more than one acidic or basic moieties, thecompounds of the present invention may include mono, di or tri-salts ina single compound.

[0133] Those compounds of the present invention that are acidic innature are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline earth metal salts and, particularly, the calcium, magnesium,sodium and potassium salts of the compounds of the present invention.

[0134] In the compounds of formula 1, where terms such as (CR¹R²)_(q)(or (CR¹R²)_(t) are used, R¹ and R² may vary with each iteration of q ort above 1. For instance, where q or t is 2, the terms (CR¹R²)_(q) or(CR¹R²)_(t) may equal —CH₂CH₂—, or —CH(CH₃)C(CH₂CH₃)(CH₂CH₂CH₃)—, or anynumber of similar moieties falling within the scope of the definitionsof R¹ and R². Further, as noted above, any substituents comprising a CH₃(methyl), CH₂ (methylene), or CH (methine) group which is not attachedto a halogeno, SO or SO₂ group or to a N, O or S atom optionally bearson said group a substituent selected from hydroxy, C₁-C₄ alkoxy and—NR¹R².

[0135] In the above compounds of formula 1, where R⁴ is—(CR¹R²)_(t)—CR¹R¹¹R¹², the R¹² group is preferably linked through acarbon atom if it is a mono-cyclic ring, and it may be linked througheither a carbon atom or a nitrogen if it is a bicyclic ring.

[0136] Certain compounds of formula 1 may have asymmetric centers andtherefore exist in different enantiomeric forms. All optical isomers andstereoisomers of the compounds of formula 1, and mixtures thereof, areconsidered to be within the scope of the invention. With respect to thecompounds of formula 1, the invention includes the use of a racemate,one or more enantiomeric forms, one or more diastereomeric forms, ormixtures thereof. The compounds of formula 1 may also exist astautomers. This invention relates to the use of all such tautomers andmixtures thereof.

[0137] The subject invention also includes isotopically-labelledcompounds, which are identical to those recited in Formula 1, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of Formula 1 of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

DETAILED DESCRIPTION OF THE INVENTION

[0138] General synthetic methods which may be referred to for preparingthe compounds of the present invention are provided in U.S. Pat. No.5,747,498 (issued May 5, 1998), U.S. patent application Ser. No.08/953,078 (filed Oct. 17, 1997), WO 98/02434 (published Jan. 22, 1998),WO 98/02438 (published Jan. 22, 1998), WO 96/40142 (published Dec. 19,1996), WO 96/09294 (published Mar. 6, 1996), WO 97/03069 (published Jan.30, 1997), WO 95/19774 (published Jul. 27, 1995) and WO 97/13771(published Apr. 17, 1997). The foregoing patents and patent applicationsare incorporated herein by reference in their entirety. Certain startingmaterials may be prepared according to methods familiar to those skilledin the art and certain synthetic modifications may be done according tomethods familiar to those skilled in the art. A standard procedure forpreparing 6-iodoquinazolinone is provided in Stevenson, T. M.,Kazmierczak, F., Leonard, N. J. , J. Org. Chem. 1986, 51, 5, p. 616.Palladium-catalyzed boronic acid couplings are described in Miyaura, N.,Yanagi, T., Suzuki, A. Syn. Comm. 1981, 11, 7, p. 513. Palladiumcatalyzed Heck couplings are described in Heck et. al. OrganicReactions, 1982, 27, 345 or Cabri et. al. in Acc. Chem. Res. 1995, 28,2. For examples of the palladium catalyzed coupling of terminal alkynesto aryl halides see: Castro et. al. J. Org. Chem. 1963, 28, 3136. orSonogashira et. al. Synthesis, 1977, 777. For formation of alkyl andcycloalkylzinc reagents, those skilled in the art may refer to Rieke, R.D., Hanson, M. V., Brown, J. D., Niu, Q. J., J. Org. Chem., 1996, 61, 8,p. 2726. Azetidinyl zinc chemistry may be carried out using methodsfound in Billotte, S. Synlett, 1998, 379. Terminal alkyne synthesis maybe performed using appropriately substituted/protected aldehydes asdescribed in: Colvin, E. W. J. et. al. Chem. Soc. Perkin Trans. 1,1977,869; Gilbert, J. C. et. al. J. Org. Chem., 47, 10, 1982; Hauske, J. R.et. al. Tet. Lett., 33, 26, 1992, 3715; Ohira, S. et. al. J. Chem. Soc.Chem. Commun., 9, 1992, 721; Trost, B. M. J. Amer. Chem. Soc., 119, 4,1997, 698; or Marshall, J. A. et. al. J. Org. Chem., 62, 13, 1997, 4313.

[0139] Alternatively terminal alkynes may be prepared by a two stepprocedure. First, the addition of the lithium anion of TMS(trimethylsilyl) acetylene to an appropriately substituted/protectedketone or aldehyde as in: Nakatani, K. et. al. Tetrahedron, 49, 9, 1993,1901. Subsequent deprotection by base may then be used to isolate theintermediate terminal alkyne as in Malacria, M.; Tetrahedron, 33, 1977,2813; or White, J. D. et. al. Tet. Lett., 31, 1, 1990, 59. Preparationof aryl amines such as phenoxyanilines, benzyloxyanilines,phenylsulfonylindoles, benzylindoles or benzylindazoles may be carriedout by reduction of the corresponding nitro intermediates. Reduction ofaromatic nitro groups may be performed by methods outlined in Brown, R.K., Nelson, N. A. J. Org. Chem. 1954, p. 5149; Yuste, R., Saldana, M,Walls, F., Tet. Lett. 1982, 23, 2, p. 147; or in WO 96/09294, referredto above. Nitro substituted N1-phenylsulfonylindoles/indazoles may beprepared by the methods found in Sundberg, R. J., Bloom, J. D., J. Org.Chem. 1980, 45, 17, p. 3382; Ottoni, 0. et al. Tetrahedron, 1998, 54,13915; or Boger, Dale L. et. al.; J. Org. Chem. 55, 4, 1990, 1379.Substituted nitro N1-benzylindoles/indazoles may be prepared by methodsfound in Makosza, M.; Owczarczyk, Z.; J. Org. Chem., 54, 21, 1989, 5094;Adebayo, Adelaide T. 0. M. et al., J. Chem. Soc. Perkin Trans. 1, 1989,1415; or WO 98/02434, referred to above. Benzyloxy-nitrobenzeneintermediates may prepared by methods found in WO 98/02434, referred toabove. Alternatively, arylmethoxy, or aryloxy nitrobenzene derivativesmay be prepared from halo nitrobenzene precursors by nucleophilicdisplacement of the halide with an appropriate alcohol as described inDinsmore, C. J. et. al., Bioorg. Med. Chem. Lett., 7, 10, 1997, 1345;Loupy, A. et. al., Synth. Commun., 20, 18, 1990, 2855; or Brunelle, D.J., Tet. Lett., 25, 32, 1984, 3383.

[0140] Starting materials, the synthesis of which is not specificallydescribed above, are either commercially available or can be preparedusing methods well known to those of skill in the art.

[0141] In each of the reactions discussed or illustrated in the Schemesabove, pressure is not critical unless otherwise indicated. Pressuresfrom about 0.5 atmospheres to about 5 atmospheres are generallyacceptable, and ambient pressure, i.e., about 1 atmosphere, is preferredas a matter of convenience.

[0142] Where the compound of formula HNR¹R³ is an optionally substitutedindole or indoline moiety, such compounds can be prepared according toone or more methods known to those skilled in the art. Such methods aredescribed in PCT international patent application publication number WO95/23141 and in W. C. Sumpter and F. M. Miller, “Heterocyclic Compoundswith Indole and Carbazole Systems,” in volume 8 of “The Chemistry ofHeterocyclic Compounds”, Interscience Publishers Inc., New York (1954).Optional substituents may be included as appropriate before or after thecoupling step illustrated in Scheme 1. Prior to the coupling step,primary and secondary amino moieties (other than said amine of formulaHNR¹R³) are preferably protected using a, nitrogen protecting groupknown to those skilled in the art. Such protecting groups and their useare described in T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” Second Edition, John Wiley & Sons, New York, 1991.

[0143] With reference to Scheme 1 above, the compound of formula 1 maybe prepared by coupling the compound of formula 2, wherein X, A, and R⁴are as defined above and Z is a leaving group, such as a substitutedphenoxy derivative (such substituents may include halo, cyano, nitro,and/or C₁-C₆ alkyl groups) or chloro, with an amine of formula 3,wherein R¹ and R³ are as defined above, in an anhydrous solvent solvent,in particular a solvent selected from DMF (N,N-dimethylformamide), DME(ethylene glycol dimethyl ether), DCE (dichloroethane), t-butanol, andphenol, or a mixture of the foregoing solvents, a temperature within therange of about 50-150° C. for a period ranging from 1 hour to 48 hours.The compound of formula 3 may be prepared by methods known to thoseskilled in the art, such as reduction of nitriles, reduction of iminesor enamines, reduction of oximes, primary and secondary amides,reduction of a nitro group or reductive amination of either R¹NH₂ andR³CH(O) or R³NH₂ and R¹CH(O). The compound of formula 2 may be preparedby treating a compound of formula 4, referred to in Scheme 2, wherein Z¹is an activating group, such as bromo, iodo, —N₂, or —OTF (which is—OSO₂CF₃), or the precursor of an activating group such as NO₂, NH₂ orOH., with a coupling partner, such as a terminal alkyne, terminalalkene, vinyl halide, vinyl stannane, vinylborane, alkyl borane, or analkyl or alkenyl zinc reagent.

[0144] In the alternative, compounds of the formula 1 may be preparedaccording to the synthesis outlined in Scheme 2. In Scheme 2, a compoundof formula 8 wherein X is NH may be prepared from a compound of formula9, wherein A and Z¹ are as defined above and Z³ is NH₂, C₁-C₆ alkoxy orOH, according to one or more procedures described in WO 95/19774,referred to above, and a compound of formula 8 wherein X is CH may beprepared from a compound of formula 10, wherein A and Z¹ are as definedabove, according to the procedure described in WO 95/19774, referred toabove. The compound of formula 8 may be converted to the compound offormula 7 by treating the starting compound with a chlorinating reagent,such as POCl₃ or ClC(O)C(O)Cl/DMF in a halogenated solvent at atemperature ranging from about 60° C. to 150° C. for a period rangingfrom about 2 to 24 hours. The compound of formula 7 may be converted tothe compound of formula 6 wherein Z is a substituted phenoxy derivativeby treating the starting compound with an appropriate metal phenoxide,such as sodium phenolate, in a solvent, such as DMF or phenol, at atemperature ranging from about 0° C. to 100° C. for a period rangingfrom about 2 to 24 hours. The compound of formula 6 may be reacted witha coupling partner such as a terminal alkyne, terminal alkene, vinylhalide, vinyl stannane, vinylborane, alkyl borane, or an alkyl oralkenyl zinc reagent, to provide a compound of the formula 2. Thecompound of formula 2 can then be transformed into a compound of formula1 by coupling with an amine of the formula 3. Alternatively, thecompound of formula 1 may be prepared by reaction of a terminal alkyne,terminal alkene, vinyl halide, vinyl stannane, vinylborane, alkylborane, or an alkyl or alkenyl zinc reagent with a compound of theformula 7 to provide an intermediate of formula 11. Intermediate 11 cansubsequently be coupled with an amine of the formula 3 to provide thecompound of formula 1. Yet another alternative method for the synthesisof derivatives of formula 1 involves the coupling of chloroquinazoline 7with amine 3 followed by subsequent coupling of intermediate 5 with aterminal alkyne, terminal alkene, vinyl halide, vinyl stannane,vinylborane, alkyl borane, or an alkyl or alkenyl zinc reagent.

[0145] The compounds of the present invention may have asymmetric carbonatoms. Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixtures into a diastereomricmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomeric mixtures andpure enantiomers are considered as part of the invention.

[0146] The compounds of formulas 1 that are basic in nature are capableof forming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate the compound of formula 1 from the reaction mixture asa pharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent, such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is readily obtained. The desired acidsalt can also be precipitated from a solution of the free base in anorganic solvent by adding to the solution an appropriate mineral ororganic acid.

[0147] Those compounds of formula 1 that are acidic in nature arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of formula 1. Suchnon-toxic base salts include those derived from such pharmacologicallyacceptable cations as sodium, potassium calcium and magnesium, etc.These salts can easily be prepared by treating the corresponding acidiccompounds with an aqueous solution containing the desiredpharmacologically acceptable cations, and then evaporating the resultingsolution to dryness, preferably under reduced pressure. Alternatively,they may also be prepared by mixing lower alkanolic solutions of theacidic compounds and the desired alkali metal alkoxide together, andthen evaporating the resulting solution to dryness in the same manner asbefore. In either case, stoichiometric quantities of reagents arepreferably employed in order to ensure completeness of reaction andmaximum yields of the desired final product. Since a single compound ofthe present invention may include more than one acidic or basicmoieties, the compounds of the present invention may include mono, di ortri-salts in a single compound.

[0148] The compounds of the present invention are potent inhibitors ofthe erbB family of oncogenic and protooncogenic protein tyrosine kinasessuch as epidermal growth factor receptor (EGFR), erbB2, HER3, or HER4and thus are all adapted to therapeutic use as antiproliferative agents(e.g., anticancer) in mammals, particularly in humans. In particular,the compounds of the present invention are useful in the prevention andtreatment of a variety of human hyperproliferative disorders such asmalignant and benign tumors of the liver, kidney, bladder, breast,gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval,thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, andother hyperplastic conditions such as benign hyperplasia of the skin(e.g., psoriasis) and benign hyperplasia of the prostate (e, BPH). Itis, in addition, expected that a compound of the present invention maypossess activity against a range of leukemias and lymphoid malignancies.

[0149] The compounds of the present invention may also be useful in thetreatment of additional disorders in which aberrant expressionligand/receptor interactions or activation or signalling events relatedto various protein tyrosine kinases, are involved. Such disorders mayinclude those of neuronal, glial, astrocytal, hypothalamic, and otherglandular, macrophagal, epithelial, stromal, and blastocoelic nature inwhich aberrant function, expression, activation or signalling of theerbB tyrosine kinases are involved. In addition, the compounds of thepresent invention may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases that are inhibited by the compounds ofthe present invention.

[0150] The in vitro activity of the compounds of formula 1 may bedetermined by the following procedure.

[0151] The c-erbB2 kinase assay is similar to that described previouslyin Schrang et. al. Anal. Biochem. 211, 1993, p233-239. Nunc MaxiSorp96-well plates are coated by incubation overnight at 37° C. with 100 mLper well of 0.25 mg/mL Poly (Glu, Tyr) 4:1 (PGT) (Sigma Chemical Co.,St. Louis, Mo.) in PBS (phosphate buffered saline). Excess PGT isremoved by aspiration, and the plate is washed three times with washbuffer (0.1% Tween 20 in PBS). The kinase reaction is performed in 50 mLof 50 mM HEPES (pH 7.5) containing 125 mM sodium chloride, 10 mMmagnesium chloride, 0.1 mM sodium orthovanadate, 1 mM ATP, 0.48 mg/mL(24 ng/well) c-erbB2 intracellular domain. The intracellular domain ofthe erbB2 tyrosine kinase (amino acids 674-1255) is expressed as a GSTfusion protein in Baculovirus and purified by binding to and elutionfrom glutathione coated beads. The compound in DMSO (dimethylsulfoxide)is added to give a final DMSO concentration of about 2.5%.Phosphorylation was initiated by addition of ATP (adenosinetriphosphate) and proceeded for 6 minutes at room temperature, withconstant shaking. The kinase reaction is terminated by aspiration of thereaction mixture and subsequent washing with wash buffer (see above).Phosphorylated PGT is measured by 25 minutes of incubation with 50 mLper well HRP-conjugated PY54 (Oncogene Science Inc. Uniondale, N.Y.)antiphosphotyrosine antibody, diluted to 0.2 mg/mL in blocking buffer(3% BSA and 0.05% Tween 20 in PBS). Antibody is removed by aspiration,and the plate is washed 4 times with wash buffer. The calorimetricsignal is developed by addition of TMB Microwell Peroxidase Substrate(Kirkegaard and Perry, Gaithersburg, Md.), 50 mL per well, and stoppedby the addition of 0.09 M sulfuric acid, 50 mL per well. Phosphotyrosineis estimated by measurement of absorbance at 450 nm. The signal forcontrols is typically 0.6-1.2 absorbance units, with essentially nobackground in wells without the PGT substrate and is proportional to thetime of incubation for 10 minutes. Inhibitors were identified byreduction of signal relative to wells without inhibitor and IC₅₀ valuescorresponding to the concentration of compound required for 50%inhibition are determined.

[0152] The activity of the compounds of formula 1, in vivo, can bedetermine by the amount of inhibition of tumor growth by a test compoundrelative to a control. The tumor growth inhibitory effects of variouscompounds are measured according to the method of Corbett T. H., et al.,“Tumor Induction Relationships in Development of Transplantable Cancersof the Colon in Mice for Chemotherapy Assays, with a Note on CarcinogenStructure”, Cancer Res., 35, 2434-2439 (1975) and Corbett T. H., et al.,“A Mouse Colon-tumor Model for Experimental Therapy”, Cancer Chemother.Rep. (Part 2)”, 5, 169-186 (1975), with slight modifications. Tumors areinduced in the left flank by subcutaneous (sc) injection of 1-5 millionlog phase cultured tumor cells (murine FRE-ErbB2 cells or human SK-OV3ovarian carcinoma cells) suspended in 0.1 ml RPMI 1640 medium. Aftersufficient time has elapsed for the tumors to become palpable (100-150mm3 in size/5-6 mm in diameter) the test animals (athymic female mice)are treated with test compound (formulated at a concentration of 10 to15 mg/ml in 5 Gelucire) by the intraperitoneal (ip) or oral (po) routeof administration once or twice daily for 7 to 10 consecutive days. Inorder to determine an anti-tumor effect, the tumor is measured inmillimeters with a Vernier caliper across two diameters and the tumorsize (mm3) is calculated using the formula: Tumor size(mm3)=(length×[width]2)/2, according to the methods of Geran, R. I., etal. “Protocols for Screening Chemical Agents and Natural ProductsAgainst Animal Tumors and Other Biological Systems”, Third Edition,Cancer Chemother. Rep., 3, 1-104 (1972). Results are expressed aspercent inhibition, according to the formula: Inhibition(%)=(TuW_(control)−TuW_(test))/TuW_(control)×100%. The flank site oftumor implantation provides reproducible dose/response effects for avariety of chemotherapeutic agents, and the method of measurement (tumordiameter) is a reliable method for assessing tumor growth rates.

[0153] Administration of the compounds of the present invention(hereinafter the “active compound(s)”) can be effected by any methodthat enables delivery of the compounds to the site of action. Thesemethods include oral routes, intraduodenal routes, parenteral injection(including intravenous, subcutaneous, intramuscular, intravascular orinfusion), topical, and rectal administration.

[0154] The amount of the active compound administered will be dependenton the subject being treated, the severity of the disorder or condition,the rate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to about 7 g/day,preferably about 0.2 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

[0155] The active compound may be applied as a sole therapy or mayinvolve one or more other anti-tumour substances, for example thoseselected from, for example, mitotic inhibitors, for example vinblastine;alkylating agents, for example cis-platin, carboplatin andcyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosinearabinoside and hydroxyurea, or, for example, one of the preferredanti-metabolites disclosed in European Patent Application No. 239362such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

[0156] The pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

[0157] Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

[0158] Suitable pharmaceutical carriers include inert diluents orfillers, water and various organic solvents. The pharmaceuticalcompositions may, if desired, contain additional ingredients such asflavorings, binders, excipients and the like. Thus for oraladministration, tablets containing various excipients, such as citricacid may be employed together with various disintegrants such as starch,alginic acid and certain complex silicates and with binding agents suchas sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, sodium lauryl sulfate and talc are often useful fortableting purposes. Solid compositions of a similar type may also beemployed in soft and hard filled gelatin capsules. Preferred materials,therefor, include lactose or milk sugar and high molecular weightpolyethylene glycols. When aqueous suspensions or elixirs are desiredfor oral administration the active compound therein may be combined withvarious sweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

[0159] Methods of preparing various pharmaceutical compositions with aspecific amount of active compound are known, or will be apparent, tothose skilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

[0160] The examples and preparations provided below further illustrateand exemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

[0161] Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a ZORBAXTM RXC18 column (manufacturedby Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. Thesamples are run on a Hewlett Packard-1100 system. A gradient solventmethod is used running 100 percent ammonium acetate/acetic acid buffer(0.2 M) to 100 percent acetonitrile over 10 minutes. The system thenproceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutesand then 100 percent buffer solution for 3 minutes. The flow rate overthis period is a constant 3 ml/minute.

[0162] In the following examples and preparations, “Et” means ethyl,“Ac” means acetyl, “Me” means methyl, and “Bu” means butyl.

[0163] Preparation of 3-methyl-4-phenoxynitrobenzene

[0164] Sodium hydride (95% dry powder) (83.62 g, 3.31 moles, 1.3 eq.)was charged under nitrogen atmosphere to a clean and dry 12 L four neckflask equipped with a condenser, a dropping funnel, a mechanical stirrerand two nitrogen inlet-outlet bubblers (Caution: sodium hydride ispyrophoric, avoid contact with water or moisture). The reaction flaskwas cooled to 0° C. (ice bath) then anhydrous DMF (1280 mL) wascarefully added using a dropping funnel. The reaction mixture wasstirred for 30 minutes at 0° C., then a solution of phenol (263.5 g, 2.8moles, 1.1 eq.) in anhydrous DMF (1280 mL) was added using a droppingfunnel over 2 hours (Caution: exothermic, vigorous hydrogen evolution).After complete addition, the reaction mixture was stirred for 40 minutesat 0° C. (the reaction mixture turned to a white slurry), then asolution of 3-methyl-4-fluoronitrobenzene (390.0 g, 2.51 moles, 1.0 eq.)in anhydrous DMF (dimethylformamide)(1280 mL) was added dropwise over 1hour. The reaction mixture was slowly warmed to room temperature andstirred at room temperature for 15-22 hours (dark-brown viscoussolution) until all the starting material was converted to thephenoxynitrotoluene (TLC, 2% ethyl acetate in hexanes). Again thereaction mixture was cooled to 0° C. (ice bath), then carefully quenchedwith cold water (5000 mL) over 2 hours (Caution: exothermic, hydrogenevolution; first 100 ml water was added over 90 minutes). The reactionmixture was stirred for 1 h, then transferred to a two 50 L carboys,each containing 40 L of water. The contents was stirred and left at roomtemperature for 24 hours to afford the phenoxynitrotoluene, as a yellowsolid. The yellow solid was filtered, washed with excess of water andair dried to afford 3-methyl-4-phenoxynitrobenzene (552 g, 96% yield).The crude 3-methyl-4-phenoxynitrobenzene was found to be pure by ¹H and¹³C NMR spectra, and used as such in the next reaction; m p 51-52° C.;FT-IR (cm⁻¹): 1582, 1509, 1480, 1339, 1242, 1204, 1091 and 796; ¹H NMR(300 MHz, CDCl₃) δ 2.41 (s, 3H), 6.78 (d, 1H, J=8.7 Hz), 7.02-7.08 (m,2H), 7.19-7.29 (m, 1H), 7.38-7.46 (m, 2H), 7.99 (dd, 1H, J=9.15 Hz, 2.7Hz); ¹³C NMR (75.45 MHz, CDCl₃) 16.22, 115.93, 119.11, 123.17, 124.9,126.79, 129.53, 130.28, 142.66, 155.44 and 161.4.

[0165] Preparation of 3-methyl-4-phenoxyaniline Hydrochloride

[0166] To a stirred solution of 3-methyl-4-phenoxynitrobenzene (2) (548g, 2.39 moles, 1.0 eq.) in methanol (5 L) was added 10% Pd/C (100 g, 50%wet, 46.98 mmol, 0.02 eq.). Then the reaction mixture was stirred undera hydrogen atmosphere (60-80 psi) for 15-16 hours at room temperature ina 2 gallon Parr hydrogenator. The progress of the reaction was monitoredby TLC (50% ethyl acetate in hexanes, sm Rf=0.69, pr Rf=0.47, UVvisible). Then the reaction mixture was filtered through Celite, and thesolid was washed with excess methanol. The filtrate was concentratedunder reduced pressure to give 3-methyl-4-phenoxyaniline as a pale brownviscous liquid (451.0 g, 95%). The 3-methyl-4-phenoxyaniline was foundto be pure by ¹H and ¹³C NMR spectra, and used as such in the nextreaction

[0167] To a cooled (0° C.) and stirred solution of3-methyl-4-phenoxyaniline (451.0 g, 2.26 moles, 1.0 eq.) in anhydrousether (12 L) was bubbled dry HCl gas for 40-90 minutes until all thestarting material was converted to the aniline hydrochloride salt. Theoff-white solid was filtered, washed with ether and dried in a vacuumoven for 6 hours at 60° C. to afford 3-methyl-4-phenoxyanilinehydrochloride (511.8 g, 96%); m p 173-174° C.; FT-IR (cm⁻¹): 3058, 3019,2840, 2573, 1485, 1253, 1223 and 691; ¹H NMR (300 MHz, CDCl₃) δ 2.22 (s,3H), 6.81-6.9 (m, 3H), 7.04-7.11 (m, 1H), 7.25-7.37 (m, 3H), 7.43 (d,1H, J=2.4 Hz), 10.45 (s, 3H); ¹³C NMR (75.45 MHz, CDCl₃) 16.03, 118.01,119.9, 122.12, 123.35, 124.78, 126.13, 129.93, 131.89, 155.5 and 156.96;APCI (negative FAB) 200.3 (100%); Anal. Calcd for C₁₃H₁₄ClNO: C, 66.24;H, 5.99; N, 5.94. Found: C, 60.05; H, 6.01; N, 5.98.

[0168] Examples of other amines prepared by the above methods are:

[0169] 3-Chloro-4-phenoxy-phenylamine

[0170] 3-Methoxy-4-phenoxy-phenylamine

[0171] 4-Phenoxy-3-trifluoromethyl-phenylamine

[0172] 3-Fluoro-4-phenoxy-phenylamine

[0173] 5-Amino-2-phenoxy-benzonitrile

[0174] 4-(2-Methoxy-phenoxy)-3-methyl-phenylamine

[0175] 4-(3-Methoxy-phenoxy)-3-methyl-phenylamine

[0176] 4-(4-Methoxy-phenoxy)-3-methyl-phenylamine

[0177] 4-(2-Fluoro-phenoxy)-3-methyl-phenylamine

[0178] 4-(3-Fluoro-phenoxy)-3-methyl-phenylamine

[0179] 4-(4-Fluoro-phenoxy)-3-methyl-phenylamine

[0180] 4-(2-Methyl-phenoxy)-3-methyl-phenylamine

[0181] 4-(3-Methyl-phenoxy)-3-methyl-phenylamine

[0182] 4-(4-Methyl-phenoxy)-3-methyl-phenylamine

[0183] 4-(2,6-Difluoro-phenoxy)-3-methyl-phenylamine

[0184] 3,5-Dichloro-4-phenoxy-phenylamine

[0185] 3-Methyl-4-phenylsulfanyl-phenylamine

[0186] 4-phenylsulfanyl-phenylamine

[0187] 4-Cyclohexyloxy-3-methyl-phenylamine

[0188] 4-Cyclopentyloxy-3-methyl-phenylamine

[0189] 4-Cyclobutyloxy-3-methyl-phenylamine

[0190] 2-Fluoro-4-phenoxyamine

[0191] 4-Fluoro-2-phenoxyamine

[0192] 3-Bromo-4-phenoxy-phenylamine

[0193] 4-(2-Chloro-phenoxy)-3-methyl-phenylamine

[0194] 4-(2-Methoxy-phenoxy)-3-methyl-phenylamine

[0195] 4-(2-Ethyl-phenoxy)-3-methyl-phenylamine

[0196] 4-(2-Trifluoromethyl-phenoxy)-3-methyl-phenylamine

[0197] 1-(5-amino-2-phenoxy-phenyl)-ethanone

[0198] (+/−)-4-Benzenesulfinyl-3-methyl-phenylamine, (+/−)4-Benzenesulfinyl-phenylamine, 4-Benzenesulfonyl-3-methyl-phenylamine,4-Benzenesulfonyl-phenylamine were prepared from3-Methyl-4-phenylsulfanyl-phenylamine and 4-phenylsulfanyl-phenylamineby oxidation methods known to those skilled in the art.

[0199] 3-Ethyl-4-phenoxy-phenylamine

[0200] To a solution of 1-(5-amino-2-phenoxy-phenyl)-ethanone (0.5 g,2.20 mmol) in THF (15 ml) was added sodium borohydride(0.4 g, 10.5 mmol)and AlCl₃ (anhydrous) (0.803 g, 6.02 mmol) under nitrogen. The resultingreaction mixture was heated under reflux for 4 hours. The mixture wasthen cooled and iced-water added. The resultant mixture was extractedwith EtOAc and dried over Na₂SO₄. Removal of the solvent afforded abrownish residue which was chromatographed with 4:1 hexane/EtOAc toafford (15 mg, 10%) product 3-ethyl-4-phenoxy-phenylamine.

[0201] 3-Hydroxy4-phenoxy-phenylamine

[0202] 3-methoxy-4-phenoxynitrobenzene(2 g, 8.15 mmol) was treated with48% HBr (20 ml) and HOAc (20 ml), The reaction mixture was heated to110° C. for 24 hours and then the reaction mixture was poured into iceand extracted with EtOAc, the organic layer was washed with brine, driedover Na₂SO₄. Removal of the solvent provided a brownish residue5-Nitro-2-phenoxy-phenol which was taken to next step without furtherpurification. (almost quantitative yield). ¹H NMR(CDCl₃): δ 7.91(d, 1H,2.7 Hz), 7.72(dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 7.43 (t, 2H, J=7.9 Hz),7.28(d, 1H, 7.9 Hz), 7.10(d, 1H, J=8.3 Hz), 6.78(d, 2H, J=8.9 Hz).

[0203] Ethoxy-4-phenoxy-phenylamine

[0204] To a solution of 5-nitro-2-phenoxy-phenol (500 mg, 2.16 mmol) inacetone(20 ml) was added bromoethane (0.353 g, 3.26 mmol) and potassiumcarbonate (0.447 g, 3.26 mmol). The resulting reaction mixture wasstirred at room temperature for 2 hours and then the reaction was heatedto 50° C. for 4 hours. Water was added and aqueous layer extracted withEtOAc (3×30 ml), the organic layer washed with brine and dried overNa₂SO₄. Removal of the solvent provided (0.3 g, 53%)3-ethoxy-4-pheoxy-nitrobenzene. The product was subjected tohygrogenation over %Pd-C in methanol to afford (0.1 g, 38%) of3-Ethoxy-4-phenoxy-phenylamine. M/z, 230.0, ¹H NMR(CDCl₃): 7.91 (d, 1H,2.7 Hz), 7.72 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 7.43 (app t, 2H, J=7.9Hz), 7.28 (d, 1H, 7.9 Hz), 7.10 (d, 1H, J=8.3 Hz), 6.78 (d, 2H, J=8.9Hz), 4.17 (dd, 2H, J1=13.9 HZ, J2=7.1 Hz), 1.42 (t, 3H, J=7.1 Hz).

[0205] 3-Isopropoxy-4-phenoxy-phenylamine was also prepared by the abovealkylation protocol.

[0206] 3-Phenyl-1H-indazol-6-ylamine

[0207] To a solution of 2-chloro-5-nitro-benzophenone (1.0 g) in THF(tetrahydrofuran) (15 ml) was added anhydrous hydrazine (120 mg). Theresulting reaction mixture was kept stirring at room temperature for 2-4hours. The solvent was removed in vacuo and the residue dissolved inEtOAc, washed with water and brine, dried over Na₂SO₄. Removal of thesolvent afforded (0.8 g, 88%) product 6-Nitro-3-phenyl-1H-indazole(5).6-Nitro-3-phenyl-1H-indazole was hydrogenated over H₂/Pd and gave 0.5 gof 3-phenyl-1H-indazol-6-ylamine (71.5%). M/z: 210.0. ¹H NMR(CD₃OD):7.86 (d, 2H, J=7.9 Hz), 7.47 (t, J=8.1 Hz), 7.35 (t, 3H, J=8.7 Hz), 7.01(d, 1H, J=8.7 Hz).

[0208] General Procedure for the Addition of1-Lithio-2-trimethylsilylacetylene to a Carbonyl

[0209] A cold (−78° C.), stirred solution of (trimethylsilyl)acetylene(1.2 eq) in anhydrous THF was treated with nBuLi (1.2 eq) under nitrogen(In the case of BOC-protected amino aldehydes containing a free NH, theamount of (trimethylsilyl)acetylene and n-BuLi is doubled.). Thecolorless solution was stirred for 30 to 40 minutes, followed by theaddition of carbonyl compounds (1.0 eq) in anhydrous THF. The reactionwas warmed up to room temperature, stirred for 2 to 4 hours, andquenched with water. After removal of THF, the residue was partitionedbetween ether or EtOAc and water. The separated organic layer was washedwith brine, dried over sodium sulfate, and concentrated to give thecrude TMS protected propargyl alcohol. Subsequently, a mixture of thecrude propargyl alcohol (1.0 eq) and K₂CO₃ (2.0 eq) in methanol wasstirred at room temperature for 0.5 to 1 hour. The solids was filteredoff and washed with ether. The filtrate was concentrated, dissolved inether, washed with water and brine, and dried over sodium sulfate.Solvent removal gave the crude terminal acetylene product, which waspurified by distillation or chromatography (Ethyl Acetate/Hexanes).Overall yields for this procedure range from 62-97%.

[0210] Examples of terminal alkynes prepared by above method are:

[0211] 3-Ethynyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

[0212] 4-Ethynyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

[0213] 3-Ethynyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester

[0214]endo-α-3-Ethynyl-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

[0215] exo-β-3-Ethynyl-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

[0216] 2-(1-Hydroxy-prop-2-ynyl)-pyrrolidine-1-carboxylic acidtert-butyl ester

[0217] 1-Cyclobutyl-prop-2-yn-1-ol

[0218] Pent-1-yn-3-ol

[0219] 4-Amino-pent-1-yn-3-ol

[0220] 1-(3-Aza-bicyclo[3.1.0]hex-6-yl)-prop-2-yn-1-ol

[0221] 4-Ethynyl-tetrahydro-pyran-4-ol

[0222] (4-Ethynyl-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester

[0223] 2-(1-Hydroxy-prop-2-ynyl)-piperidine-1-carboxylic acid tert-butylester

[0224] 3-(1-Hydroxy-prop-2-ynyl)-piperidine-1-carboxylic acid tert-butylester

[0225] 4-Ethynyl-1-methyl-piperidin4-ol

[0226] (2-Hydroxy-but-3-ynyl)-methyl-carbamic acid tert-butyl ester

[0227] (2-Ethynyl-2-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester

[0228] R and S-3-Ethynyl-1-aza-bicyclo[2.2.2]octan-3-ol

[0229] General Procedure Homologating Aldehydes to Terminal Alkynes

[0230] To a cold (−78° C.), stirred solution of LDA (lithiumdiisopropylamide) (1.3 eq) in anhydrous THF was added a solution of(trimethylsilyl)diazomethane in hexane (1.3 eq) dropwise under nitrogen(In the case of BOC-protected amino aldehydes containing a free NH, theamount of (trimethylsilyl)diazomethane and LDA is doubled.). After 1hour, aldehyde (1.0 eq) in anhydrous THF was introduced and cooling bathwas removed. The reaction was stirred at rt for Ito 2 hours, quenchedwith water, concentrated, and partitioned between ether and water. Theseparated organic layer was washed with brine, dried over sodiumsulfate, and concentrated to give the crude product, which was purifiedby distillation or chromatography (Ethyl Acetate/Hexanes). Overallyields for this procedure range from 37-72%.

[0231] Examples of terminal alkynes prepared by this method are:

[0232] 4-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester

[0233] 3(S)-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester

[0234] 3(R)-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester

[0235] 2-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester

[0236] 3-Ethynyl-pyrrolidine-1-carboxylic acid tert-butyl ester

[0237] 3-Ethynyl-azetidine-1-carboxylic acid tert-butyl ester

[0238] (4-Ethynyl-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester

[0239] [1-(tert-Butyl-dimethyl-silanyloxymethyl)-prop-2-ynyl]-carbamicacid tert-butyl ester

[0240] 4-Prop-2-ynyl-piperazine-1-carboxylic Acid Tert-Butyl Ester

[0241] To a solution of N-t-butoxycarbonypiperazine (5.0 g, 26.8 mmol)in acetone (40 ml) was added potassium carbonate (3.70 g, 26.8 mmol).Propargyl bromide (2.39 ml, 26.8 mmol) in acetone (10 ml) was addeddropwise to the above reaction mixture. The resultant mixture wasallowed to stir at room temperature for overnight. Water was added, theaqueous layer extracted with ether and combined organic layer washedwith brine, dried over sodium sulfate and concentrated in vacuo toafford 4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester whichas crude material is taken on into a Pd coupling reaction with theappropriate anilinoquinazoline.

[0242] Examples of terminal alkynes prepared by this method are:

[0243] 1-Prop-2-ynyl-pyrrolidine

[0244] 3-Methyl-4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butylester

[0245] 3,5-Dimethyl-4-prop-2-ynyl-piperazine-1-carboxylic acidtert-butyl ester

[0246] 1-Methyl-4-prop-2-ynyl-piperazine

[0247] 4-Prop-2-ynyl-morpholine

[0248] (3-Prop-2-ynyl-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol

[0249] 1-Prop-2-ynyl-piperidin-4-ol

[0250] 1-Prop-2-ynyl-piperidin-3-ol

[0251] 1-Prop-2-ynyl-pyrrol id in-3-ol

[0252] (1-Prop-2-ynyl-piperidin-4-yl)-methanol

[0253] (1-Prop-2-ynyl-piperidin-3-yl)-methanol

[0254] (1-Prop-2-ynyl-piperidin-2-yl)-methanol

[0255] (1-Prop-2-ynyl-pyrrolidin-2-yl)-methanol

[0256] 2-(1-Prop-2-ynyl-piperidin-4-yl)-ethanol

[0257] 2-(4-Prop-2-ynyl-piperazin-1-yl)-ethanol

[0258] 4,4-Dimethoxy-1-prop-2-ynyl-piperidine

[0259] 1-Prop-2-ynyl-piperidin-4-ylamine

[0260] 2-(Methyl-prop-2-ynyl-amino)-ethanol

[0261] 4-Prop-2-ynyl-piperazine-1-carboxylic acid methylamide

[0262] 1-(4-Prop-2-ynyl-piperazin-1-yl)-ethanone

[0263] 4-Prop-2-ynyl-piperazine-1-carboxamide

[0264] 1-Methanesulfonyl-4-prop-2-ynyl-piperazine

[0265] 2-Chloro-N-prop-2-ynyl-acetamide

[0266] Propargyl amine (250 mg; 0.34 ml; 4.6 mmol) was dissolved indichloromethane (10 ml) and cooled to 0° C. Chloro-acetyl chloride (256mg; 0.18 ml; 2.3 mmol) was added to this solution dropwise and thesolution was stirred for 30 minutes and allowed to warm up to roomtemperature. The solution was washed with 2×H₂O, dried over Na₂SO₄ andthe solvent removed. 2-Chloro-N-prop-2-ynyl-acetamide (385 mg) wasobtained as white crystals. ¹H NMR (400 MHz; CDCl₃) δ 2.27 (1H, m), 4.07(2H, s), 4.09 (2H, q, J=2.5 Hz), 6.78 (1H, br s).

[0267] Examples of terminal acetylenes prepared by the above method are:

[0268] N-Prop-2-ynyl-acetamide

[0269] N-Prop-2-ynyl-propionamide

[0270] Cyclopropanecarboxylic acid prop-2-ynylamide

[0271] 2,2-Dimethyl-N-prop-2-ynyl-propionamide

[0272] N-Prop-2-ynyl-methanesulfonamide

[0273] N-Methyl-N-prop-2-ynyl-acetamide

[0274] N-(1-Methyl-prop-2-ynyl)-acetamide

[0275] N-(1,1-Dimethyl-prop-2-ynyl)-acetamide

[0276] 2-Methoxy-N-prop-2-ynyl-acetamide

[0277] 2-(tert-Butoxycarbonylamino)-2-methyl-1-propanol

[0278] A mixture of 2-amino-2-methyl-1-propanol (8.9 g, 0.1 mol),di-tert-butyldicarbonate (22.0 g, 0.1 mol), and Na₂CO₃ (21.0 g, 0.2 mol)in water/THF (150/150 mL) was refluxed for 1 hour. After removal of THF,the residue was partitioned between ether (200 mL) and water (150 mL).The separated organic layer was washed with brine (100 mL), dried oversodium sulfate, and concentrated to give 17.97 g (95%) of2-(tert-butoxycarbonylamino)-2-methyl-1-propanol as waxy, white solid:¹H NMR (CDCl₃) δ 1.23 (s, 6H), 1.41 (s, 9H), 3.56 (s, 2H).

[0279] 2-(tert-butoxycarbonylamino)-2-methyl propionaldehyde

[0280] To a solution 2-(tert-Butoxycarbonylamino)-2-methyl-1-propanol(5.7 g, 30.0 mmol) in triethylamine (42 mL) was added a mixture ofsulfur trioxide pyridine complex (14.3 g, 90.0 mmol) in anhydrous DMSO(dimethylsulfoxide) (50 mL) at room temperature. The reaction wasstirred for 1 hour under nitrogen and concentrated. The residue wasdissolved in EtOAc (200 mL), washed with water (100 mL) and brine (100mL), dried over sodium sulfate, and concentrated to give crude2-(tert-butoxycarbonylamino)-2-methyl propionaldehyde as yellow oil.Purification by distillation afforded 4.909 (87%) of waxy, white solid:¹H NMR (CDCl₃) δ 1.30 (s, 6H), 1.41 (s, 9H), 4.97 (br, 1H), 9.40 (s,1H).

[0281] 4,4-Dimethyl-5-trimethylsilylethynyl-2-oxazolidinone

[0282] A cold (−78° C.), stirred solution of (trimethylsilyl)acetylene(4.42 g, 45.0 mmol) in anhydrous THF (20 mL) was treated with nBuLi (18mL, 45.0 mmol) under nitrogen. The colorless solution was stirred for 30minutes and followed by the addition of2-(tert-butoxycarbonylamino)-2-methyl propionaldehyde (2.80 g, 15 mmol)in anhydrous THF (20 mL). The reaction was warmed up to roomtemperature, stirred for 2 hours, and quenched with water. After removalof THF, the residue was partitioned between ether (150 mL) and water(100 mL). The separated organic layer was washed with brine (100 mL),dried over sodium sulfate, and concentrated to give the crude4,4-Dimethyl-5-trimethylsilylethynyl-2-oxazolidinone (100%) as yellowoil which was carried to the next step.

[0283] 4,4-Dimethyl-5-ethynyl-2-oxazolidinone

[0284] A mixture of 4,4-Dimethyl-5-trimethylsilylethynyl-2-oxazolidinone(15.0 mmol) and K₂CO₃ (4.1 g, 30.0 mmol) in methanol (30.0 mL) wasstirred at room temperature for 30 min. The solid was filtered off andwashed with ether. The filtrate was concentrated, dissolved in ether(100 mL), washed with water (50 mL) and brine (50 mL), and dried oversodium sulfate. Solvent removal afforded 1.10 g (53%) of4,4-Dimethyl-5-ethynyl-2-oxazolidinone as a yellow oil: ¹H NMR (CDCl₃) δ1.37 (s, 3H), 1.39 (s, 3H), 2.68 (s, 1H), 4.82 (s, 1H), 6.00 (br s, 1H).

[0285] Preparation of 4-Ethynyl-4-hydroxy-tetrahydro-pyran-2-carboxylicAcid Amide

[0286] 4-Oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester: ZnCl(0.63 g, 4.6 mmol) was dissolved in anhydrous THF (15 mL) and added to asolution of 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (7.94 g, 46.0mmol) and ethyl glyoxalate (7.05 g, 69.0 mmol) in toluene (30 mL) atroom temperature. After stirring for 30 minutes, water (30 mL) and TFA(trifluoracetic acid) (2 mL) were added and the mixture was stirredvigorously for 20 min. After concentration, the residue was partitionedbetween EtOAc (200 mL) and water (100 mL). The separated organic layerwas washed with brine, dried over sodium sulfate, and concentrated togive 8.0 g (100%) of brown oil which was carried to the next stepwithout further purification. ¹H NMR (CDCl₃) δ 1.30 (t, 3H), 2.85 (d,2H), 4.26 (q, 2H), 5.00 (t, 1H), 5.48 (d, 1H), 7.39 (d, 1H).

[0287] 4-Oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester: A mixtureof 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 46.0mmol) and Pd/C (10%, 0.20 g,) in EtOAc (70 mL) was shaken in a Parrbottle with hydrogen at 50 psi overnight and filtered through a pad ofCelite. The filtrate was concentrated and the residue was distilled togive 2.629 (33%) of yellowish oil: ¹H NMR (CDCl₃) δ 1.29 (t, 3H), 2.40(d,1H), 2.58-2.75 (m 3H), 3.79 (tt, 1H), 4.23 (q, 2H), 4.28 (m 1H), 4.40(m, 1H).

[0288] 4-Hydroxy-4-trimethylsilanylethynyl-tetrahydro-pyran-2-carboxylicacid ethyl ester: A cold (-78° C.), stirred solution of(trimethylsilyl)acetylene (1.80 g, 18.24 mmol) in anhydrous THF (30 mL)was treated with nBuLi (7.3 mL in hexane, 18.24 mmol) under nitrogen.The colorless solution was stirred for 30 minutes and followed by theaddition of 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.62g, 15.2 mmol) in anhydrous THF (30 mL). The reaction was warmed up toroom temperature, stirred for 2 hours, and quenched with water (30 mL).After removal of THF, the product was extracted with EtOAc (2×60 mL).The combined organic layer was washed with brine, dried over sodiumsulfate, and concentrated to give 2.50 g (61%) of yellow oil: ¹H NMR(CDCl₃) δ 0.17 (s, 9H), 1.30 (t, 3H), 1.76-1.90 (m, 3H), 2.25 (m, 1H),3.66 (tt, 1H), 4.11-4.21 (m, 2H), 4.24 (q, 2H).

[0289] 4-Ethynyl-4-hydroxy-tetrahydro-pyran-2-carboxylic acid amide:4-Hydroxy-4-trimethylsilanylethynyl-tetrahydro-pyran-2-carboxylic acidethyl ester (2.50 g, 9.25 mmol) was dissolved in MeOH (20 mL) in apressure reaction tube and NH₃ gas was passed through the solution for10 minutes with stirring. The tube was tightly capped and the reactionwas stirred for 3 days. After solvent removal, 1.53 g (97%) of yellowoil was obtained: ¹H NMR (CD₃OD) δ 1.48 (t, 1H), 1.70 (td, 1H), 1.85 (d,1H), 2.30 (d, 1H), 3.04 (s, 1H), 3.29 (s, 1H), 3.71 (t, 1H), 3.98 (d,1H), 4.06 (dt, 1H).

[0290] Preparation of2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-ethynyl-tetrahydro-pyran-4-ol

[0291] 2-Hydroxymethyl-tetrahydro-pyran-4-ol: To a cooled (0° C.),stirred suspension of LiAlH₄ (3.42 g, 90.0 mmol) in anhydrous THF (50mL) was added dropwise a solution of 4-oxo-tetrahydro-pyran-2-carboxylicacid ethyl ester (5.17 g, 30.0 mmol). After stirring for 1 hour, thereaction was quenched by the slow, sequential addition of water (3.4mL), 15% NaOH (3.4 mL), and water (10.0 mL). The inorganic salt wasfiltered off and extracted with EtOAc repeatedly since the product wasabsorbed on the solid. Solvent removal afforded 2.42 g (61%) of yellowoil. The crude mixture was carried to the next step withoutpurification.

[0292] 2-(tert-Butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran4-ol: Toa solution of 2-hydroxymethyl-tetrahydro-pyran-4-ol (2.42 g, 18.3 mmol),DMAP (4-dimethylaminopyridine) (90 mg, 0.74 mmol), and Et₃N (2.04 g,20.1 mmol) in anhydrous CH₂Cl₂ (50 mL) was added tert-butyldimethylsilylchloride (2.76 g, 18.3 mmol) at room temperature. After stirringovernight, the reaction solution was quenched with brine (30 mL) and theseparated aqueous layer was extracted with CH₂Cl₂ (40 mL). The combinedorganic extract was dried over sodium sulfate and concentrated.Purification by silica gel column using 30% EtOAc in hexane gave 2.27 g(50%) of colorless oil: ¹H NMR (CDCl₃) δ 0.04 (s, 6H), 0.88 (s, 9H),1.21 (m, 1H), 1.43 (m, 1H), 1.82 (dt, 1H), 2.00 (dt, 1H), 3.35 (m, 1H),3.51 (q, 1H), 3.66 (q, 1H), 3.79 (m, 1H), 4.01 (m, 1H).

[0293] 2-(tert-Butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-one:A solution of2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-ol (2.27 g,9.21 mmol) in anhydrous DMSO/Et₃N (15/13 mL) was treated with sulfurtrioxide pyridine complex (7.33 g, 46.1 mmol) portionwise at roomtemperature. After stirring for 1 hour, the reaction was concentratedand the residue was partitioned between EtOAc (100 mL) and water (50ml). The separated organic layer was washed with brine (70 mL), driedover sodium sulfate, and concentrated. Purification by silica gel columnusing 10-20% of EtOAc in hexane afforded 1.48 g (66%) of colorless oil:¹H NMR (CDCl₃) δ 0.05 (s, 6H), 0.88 (s, 9H), 2.32 (dt, 1H), 2.41 (m,2H), 2.58 (m, 1H), 3.62 (m, 2H), 3.70 (d, 2H), 4.31 (m, 1H).

[0294]2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-trimethylsilanylethynyl-tetrahydro-pyran-4-ol:A cold (-78° C.), stirred solution of (trimethylsilyl)acetylene (1.01 g,10.3 mmol) in anhydrous THF (25 mL) was treated with nBuLi (4.12 mL inhexane, 10.3 mmol) under nitrogen. The colorless solution was stirredfor 30 minutes and followed by the addition of2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-one (1.48 g,6.06 mmol) in anhydrous THF (25 mL). The reaction was warmed up to roomtemperature, stirred for 2 hours, and quenched with water (30 mL). Afterremoval of THF, the product was extracted with EtOAc (2×50 mL). Thecombined organic layer was washed with brine, dried over sodium sulfate,and concentrated to give 1.75 g (84%) of yellow oil: ¹H NMR (CDCl₃) δ0.05 (s, 6H), 0.16 (s, 9H), 0.89 (s, 9H), 1.43 (m, 1H), 1.78 (td, 1H),1.83 (d, 1H), 1.94 (d, 1H), 3.52-3.70 (m, 4H), 4.00 (m 1H).

[0295]2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-ethynyl-tetrahydro-pyran4-ol:A mixture of2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trimethylsilanylethynyl-tetrahydro-pyran-4-ol(1.75 g, 5.1 mmol) and K₂CO₃ (1.4 g, 10.2 mmol) was stirred at roomtemperature for 30 minutes. After concentration, the residue waspartitioned between EtOAc (50 mL) and water (30 mL) and the separatedaqueous layer was extracted with EtOAc. The combined organic extract wasdried over sodium sulfate and concentrated to give 1.33 g (96%) of lightyellow oil: ¹H NMR (CDCl₃) δ 0.05 (s, 6H), 0.88 (s, 9H), 1.50 (m, 1H),1.78 (m, 1H), 1.84 (d, 1H), 2.01 (m, 1H), 2.55 (s, 1H), 3.55-3.70 (m,4H), 4.00 (m, 1H).

[0296] 6-Iodo-4-quinazolinone

[0297] A solution of 2-amino-5-iodobenzoic acid (26.3 g, 100 mmol) andformamidine acetate (13.5 g, 130 mmol) in ethanol (400 mL) was refluxedfor 20 hours. After cooling to 0° C., the solid product was collected byfiltration. Further drying in vacuo provided 6-iodo-4-quinazolinone(22.0 g, 81%) as a grey crystalline solid. ¹H NMR (400 MHz; DMSO-d₆) δ:12.38 (br. s, 1H), 8.35 (d, 1H), 8.05-8.10 (m, 2H), 7.43 (dd, 1H). LRMS:272.9 (MH⁺).

[0298] 6-iodo-4-chloroquinazoline (12): To a stirred solution of DMF(6.3 mL) in DCE (20 mL) cooled to 0° C. was added dropwise a solution ofoxalyl chloride (60 mL of a 2M solution in DCE). After addition wascomplete, the cooling bath was removed and 6-iodo-3H-quinazolinone (10g, 36.8 mmol) was added as a solid. The resulting mixture was heated toreflux under nitrogen for 3 hours. Upon cooling to room temperature, thereaction was quenched cautiously with H₂O. CH₂Cl₂ was added and thebilayer transferred to a separatory funnel. The aqueous layer wasextracted with CH₂Cl₂ (2×50 mL) and the combined organic layers dried(Na₂SO₄). The solvent was removed in vacuo to provide a yellow solidwhich was triturated with diethyl ether to remove any remainingimpurities. The resulting yellow solid obtained by filtration was shownto be pure by NMR. ¹ HNMR (CDCl₃, 400 MHz): δ: 9.05 (s, 1H), 8.65 (d,1H), 8.21 (dd, 1H), 7.78 (d, 1H).

[0299] 6-iodo-4-phenoxyquinazoline (13): A suspension of NaH (washedfree of mineral oil) in DMF (40 mL) was cooled to 0° C. and a solutionof phenol (5.65 g, 60 mmol) in DMF (20 mL) was added dropwise. Uponcompletion of addition, 6-iodo-4-chloroquinazoline (14.6 g, 50.3 mmol)was added as a solid in small portions. The cooling bath was moved andthe reaction mixture was stirred at room temperature for 2 hours. Themixture was then quenched with water (200 mL), diluted with EtOAc (300mL) and transferred to a separatory funnel. The organic layer was washedwith dilute aqueous NaOH, water and brine and dried over Na₂SO₄.Filtration of the solids and removal of the solvent provided quinazoline13 (17.2 g, 98%) as a yellow solid. ¹H NMR (400 MHz; CDCl₃): δ: 8.74 (d,1H), 8.14 (s, 1H), 8.12 (dd, 1H), 7.71 (d, 1H), 7.49 (dd, 2H), 7.32 (t,1H), 7.22 (m, 2H).

[0300] Method A:(1-Benzenesulfonyl-1H-indol-5-yl)-[6-(3-imidazol-1-yl-prop-1-ynyl)-quinazolin-4-yl]-amine(15).

[0301] (1-Benzenesulfonyl-1H-indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine(14): 6-iodo-4-chloroquinazoline (2.38 g, 8.20 mmol) and5-amino-1-benzenesulfonylindole (2.46 g, 9.00 mmol) were combined in DCE(20 mL) and t-butanol (20 mL). The resulting mixture was heated atreflux under nitrogen for 18 hours to form a bright yellow suspension.Upon cooling the solids were filtered and rinsed with CH₂Cl₂ and placedunder high vacuum to remove any excess solvent. Quinazoline 14 (3.23 g,75%) was obtained as a yellow solid. ¹H NMR (DMSO d6; 400 MHz): δ: 9.24(s, 1H, NH), 8.84 (s, 1H), 8.33 (dd, 1H, 8.9 Hz, 1.7 Hz), 8.01 (m, 4H),7.90 (m, 2H), 7.70 (m, 2H), 7.60 (m, 3H), 6.92 (dd, 1H, J=3.7 Hz, 0.6Hz).

[0302](1-Benzenesulfonyl-1H-indol-5-yl)-[6-(3-imidazol-1-yl-prop-1-ynyl)-quinazolin-4-yl]-amine(15): Quinazoline 14 (150 mg, 0.28 mmol), 1-N-2-propynylimidazole (200mg, 1.89 mmol), Pd(OAc)₂ (4 mg, 0.016 mmol) and PPh₃ (9 mg, 0.033 mmol)were mixed in NEt₃ (1.25 mL) and DMF (0.5 mL). The mixture was heated at80° C. under N₂ for 16 hours. Upon cooling the black suspension wasconcentrated under reduced pressure and the residue dissolved in MeOH.Silica gel (1 g) was added and the methanol removed in vacuo. Theresulting silica gel was placed atop a silica gel (40 g) column whichwas then eluted with 200 mL 50:1 CH₂Cl₂:MeOH, the 300 mL 25:1 CH₂Cl₂ toprovide alkyne 15 (72 mg, 51%) as a yellow foam. ¹H NMR (CDCl₃; 400MHz): δ: 8.95 (br, 1H, NH), 8.63 (s, 1H), 8.62 (s, 1H), 8.24 (s, 1H),7.96 (d, 1H, J=1.7 Hz), 7.84 (m, 3H), 7.71 (m, 2H), 7.51 (m, 3H), 7.41(m, 2H), 7.14 (s, 1H), 7.10 (s, 1H), 6.55 (d, 1H, J=3.5 Hz), 5.01 (s,2H).

[0303] Method A′:(3-Methyl-4-phenoxy-phenyl)-[6-(3-piperazin-1-yl-prop-1-ynyl)-quinazolin-4-yl]-amine

[0304] (6-iodo-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine: The4-chloro-6-iodo-quinazoline (5.0 g, 17.2 mmol) and the3-methyl-4-phenoxyaniline (17.2 mmol) were mixed together in 1:1dichloroethane and t-butanol (50 ml). The reaction mixture was heated at90° C. for 4 hours whereupon a yellow precipitate was observed. Thereaction was cooled down and the precipitate was collected and afforded(6-iodo-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine. (8.0 g,94%). M/z, 454. ¹H NMR (CD₃OD): δ: 9.12(s, 1H), 8.83(s, 1H), 8.39(d, 1H,J=8.8 Hz), 7.63(d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=2.1 Hz), 7.35(dd,1H,J1=J2=8.5 Hz), 7.28(t, 2H, J=8.1 Hz), 7.05 (t, J=8.5 Hz), 6.87(d, 1H,J=8.1 Hz), 3.81(s, 3H).

[0305](3-methyl-4-phenoxy-phenyl)-[6-(3-piperazin-1-yl-prop-1-ynyl)-quinazolin4-yl]-amine:The 4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester (2.37 g,crude) and (6-iodo-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine(800 mg, 1.76 mmol), Pd(OAc)₂ (23.7 mg, 0.105 mmol,), PPh₃(55.3 mg,0.21mmol) in Et₃N (8 ml) and DMF (3 ml) were mixed together. The resultingreaction mixture was heated at 80° C. for overnight. After cooling,methylene chloride was added to the reaction mixture and the darkmixture was washed with brine and dried over sodium sulfate. The solventwas removed and the residue was chromatographed on silica gel (1:1hexane+ethyl acetate) to give product 2. 2 was dissolved in methyenechloride and HCl gas was bubbled through for 5 minutes, precipitate wascollected and afforded (400 mg, 46.7%) product(3-methyl-4-phenoxy-phenyl)-[6-(3-piperazin-1-yl-prop-1-ynyl)-quinazolin-4-yl]-amine.

[0306] M/z, 450, ¹H NMR (DMSO), δ (ppm), 9.52 (s, 1H), 8.84 (s, 1H),8.20 (dd, 1H, J1=8.7 Hz, J2=1.3 Hz), 7.99 (d, 1H, J=2.5 Hz), 7.60 (dd,J1=8.7 Hz, J2=2.7 Hz), 7.36 (app t, 2H, J=8.5 Hz), 7.11 (t, 1H, J=7.5Hz), 6.92 (d, 1H, J=8.8 Hz), 6.91 (d, 1H, J=7.9 Hz). 3.55 (br, 4H), 3.44(br, 4H), 3.30 (s, 2H), 2.19 (s, 3H).

[0307] Method B: (6-Cyclobutyl-quinazolin4-yl)-(4-phenoxy-phenyl)amine(17).

[0308] 6-cyclobutyl-4-phenoxyquinazoline (16): To a stirred solution ofnaphthalene (3.85 g, 30 mmol) in dry THF (tetrahydrofuran)(20 mL) atroom temperature was added finely cut lithium metal (0.21 g, 30 mmol) insmall portions. The mixture turned dark green and stirring was continuedfor 2 hours. A solution of ZnCl₂ (33 mL of a 0.5 M solution in THF, 16.5mmol) was then added dropwise via syringe imparting a black color. After3 hours, stirring was discontinued and the fine Zn dust was allowed tosettle. The supernatant (˜40 mL) was removed with a dry pipet andreplaced with fresh THF (10 mL). Cyclobutyl bromide (2.0 g, 14.8 mmol)was then added and the resulting dark mixture allowed to stir at roomtemparature for 16 hours. Stirring was again stopped and the supernatantorganozinc reagent used immediately in the next reaction.

[0309] To a solution of 6-iodo-4-phenoxyquinazoline (1.75 g, 5.03 mmol),Pd₂(dba)₃ [tris(dibenzylideneacetamide)dipalladium(0)] (90 mg, 0.1 mmol)and trifurylphosphine (185 mg, 0.8 mmol) in THF (10 mL) was addedcyclobutyl zinc prepared as above. The resulting mixture was stirred for6 hours, then diluted with THF (30 mL) and quenched with saturated NH₄Clsolution (40 mL). The two layers were separated and the organic layerwashed with water and brine then dried (Na₂SO₄). Removal of the solidsand removal of the solvent in vacuo provided a brown oil. Purificationby silica gel chromatography eluting with 1:1 EtOAc:hexanes provided6-cyclobutyl-4-phenoxyquinazoline (0.78 g, 56%) as a yellow oil. ¹H NMR(400 MHz: CDCl₃): δ: 8.71 (s, 1H), 8.14 (s, 1H), 7.92 (d, 1H), 7.78 (dd,1H), 7.50 (t, 2H), 7.31 (t, 1H), 7.25 (d, 2H), 3.78 (m, 1H), 2.43 (m,2H), 2.25 (m, 2H), 2.11 (m, 1H), 1.92 (m, 1H).

[0310] (6-Cyclobutyl-quinazolin-4-yl)-(4-phenoxy-phenyl)amine (17):Quinazoline 16 (50 mg, 0.18 mmol) was combined with 4-phenoxyaniline (67mg, 0.36 mmol) in phenol (0.45 g). The mixture was heated at 100° C. fora total of 17 hours. Excess phenol was removed by distillation underreduced pressure to provide a residue which was triturated with CH₂Cl₂to provide the desired quinazoline 17 (20 mg, 30%) as a yellow solid. ¹HNMR (DMSO d6, 400 MHz): δ: 9.76 (s, 1H), 8.47 (s, 1H), 8.31 (s, 1H),7.77 (d, 2H), 7.69 (m, 2H), 7.36 (t, 2H), 7.11 (t, 1H), 7.03 (d, 2H),6.98 (d, 2H), 3.69 (m, 1H), 2.35 (m, 2H), 2.23 (m, 2H), 2.01 (m, 1H),1.86 (m, 1H).

[0311] Method C: cis- andtrans-3-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-cyclobutanecarboxylicacid ethyl ester (19a/19b).

[0312] cis- andtrans-3-(4-Phenoxy-quinazolin-6-yl)-cyclobutanecarboxylic acid ethylester (18a,b): To a solution of naphthalene (1.92 g, 15 mmol) in dry THFunder N₂ was added finely cut Li metal (104 mg, 15 mmol) in smallportions resulting in a green mixture which was stirred for 2 hours.Zinc Chloride (16 mL of a 0.5M solution in THF, 8 mmol) was then addeddropwise via syringe and the mixture stirred at room temperature for 3hours. Stirring was stopped and the supernatant removed and replacedwith a solution of ethyl-3-iodocyclobutane-1-carboxylate (790 mg, 3mmol). The resulting suspension was stirred for 20 hours when stirringwas stopped and the remaining Zn metal allowed to settle. The remainingsolution was then transferred to a dry flask containing quinazoline 13(520 mg, 1.5 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol) andtri-2-furylphosphine (56 mg, 0.24 mmol). The mixture was stirred at roomtemperature for 16 hours. The mixture was concentrated, and the residuetaken up in EtOAc (30 mL) and washed with saturated aqueous NH₄Cl, brineand H₂O and dried (Na₂SO₄). The solvent was removed in vacuo and theresulting residue purified by silica gel chromatography to providecyclobutyl esters 18a and 18b as a mixture of cis and trans isomers (300mg, 57%). LRMS: 349.2 (MH+). HPLC: 7.31 min (28%); 7.44 min (72%).

[0313] cis- and-trans-3-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-cyclobutanecarboxylicacid ethyl ester (19a,b): Esters 18a and 18b (300 mg, 0.86 mmol) werecombined with 5-amino-1-phenylsulfonylindole (270 mg, 1.0 mmol) andphenol (1.0 g). The mixture was heated to 100° C. for 48 hours. Theexcess phenol was removed by distillation and the residue dissolved inCH₂Cl₂, transferred to a separatory funnel and washed with H₂O andbrine. The organic layer was dried (Na₂SO₄) and the solvent removed toprovide a dark residue which was purified by preparative TLC elutingwith EtOAc to provide esters 19a and 19b (0.20 g, 44%) as a waxy solid.LRMS: 527.2 (MH⁺). HPLC: 7.54 min (16%); 7.64 min (84%).

[0314] Method D: cis- andtrans-3-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-cyclobutyl}-methanol(20a,b):

[0315] To a cold (−78° C.), stirred solution of ethyl esters 19a/19b (70mg, 0.13 mmol) in anhydrous toluene (5 mL) was added 0.78 mL of DIBAL-H(diisobutylaluminum hydride) (1 M in toluene) dropwise via syringe. Thereaction was then warmed up to 0° C., stirred for 3 hours, then quenchedby dilution with aqueous NH₄Cl. The mixture was transferred to aseparatory funnel and extracted with ethyl acetate. The organic layerwas dried (Na₂SO₄), the solids removed and the remaining filtrateconcentrated to provide an oil which was purified by preparative TLC(elute w/ethyl acetate) to give 7 mg (11%) of alcohols 20a/20b as ayellow solid: MS m/z (MH⁺) 485.2; HPLC 5.97 min.

[0316] Method E: cis- andtrans-{3-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-cyclobutyl}-pyrrolidin-1-yl-methanone(21a, b)

[0317] The ethyl esters 19a/19b (60 mg, 0.11 mmol) were dissolved inmethanol (5 mL) and refluxed for 1 hour to convert the ethyl ester tomethyl ester. After removal of methanol, the residue was dissolved inpyrrolidine (5 mL) and heated at reflux for 20 hours. Removal ofpyrrolidine gave a oily, brown product mixture which was purified bypreparative TLC (ethyl acetate elution) to give 22 mg (36%) of amides21a/21b as a waxy, yellow solid: MS m/z (MH⁺) 552.2; HPLC 6.447 min.

[0318] Method F:4-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-1-methyl-piperidin-4-ol(23).

[0319] 1-Methyl-4-(4-phenoxy-quinazolin-6-ylethynyl)-piperidin-4-ol(22): To a 100 mL round bottom flask under nitrogen were added,quinazoline 13 (1.32 g, 3.80 mmol), 4-ethynyl-1-methyl-piperidin-4-ol(1.06 g, 7.6 mmol), Pd(OAc)₂ (51 mg, 0.23 mmol), PPh₃ (120 mg, 0.46mmol) and triethylamine (18 mL). The flask was equipped with a refluxcondenser and the mixture heated to 100° C. for 16 hours. The darksolution was then cooled and the triethylamine removed under reducedpressure. The resulting residue was diluted with EtOAc (75 mL) and H₂O(25 mL) and transferred to a separatory funnel. The organic layer waswashed successively with H₂O (2×25 mL) and the combined aqueous washesback extracted with EtOAc (25 mL). The combined organic layers weredried (MgSO₄) and the solvent removed under reduced pressure. Theresulting black foam was purified on silica gel (50 g) eluting with 250mL 30:1 CH₂Cl₂:MeOH, then 400 mL 30:1:1 CH₂Cl₂:MeOH:NEt₃ to provide thedesired product as a yellow foam (930 mg, 68%). ¹H NMR: (CDCl3; 400 MHz)δ: 8.71 (s, 1H), 8.36 (d, 1H, J=1.9 Hz), 7.89 (d, 1H, J=8.7 Hz), 7.80(dd, 1H, J=8.7 Hz, 1.9 Hz), 7.45 (t, 2H, J=8.3 Hz), 7.31 (m, 1H), 7.21(m, 2H), 2.72 (br, 2H), 2.47 (br, 2H), 2.31 (s, 3H), 2.09 (m, 2H), 2.00(m, 2H).

[0320]4-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-1-methyl-piperidin-4-ol(23): In a 1 mL Wheaton vial quinazoline 22 (80 mg, 0.22 mmol) wascombined with 5-amino-1-benzylindole (54 mg, 0.24 mmol), pyridiniumhydrochloride (5 mg, 0.04 mmol) and phenol (104 mg, 1.11 mmol). The vialwas capped and heated at 100° C. for 16 hours. After cooling thecontents of the Wheaton vial were solvated in a minimal amount of EtOAcand placed atop a silica gel (5 g) column. Elution of the column with1:1:0.1 Hexanes:EtOAc/NEt₃ removed high R_(f) impurities. The desiredproduct 23 (R_(f) 0.05, 10:1 CH₂Cl₂:MeOH) was eluted off with 10:1CH₂Cl₂:MeOH and gave a yellow solid (65 mg, 60%). ¹H NMR (DMSO d6; 400MHz): δ: 9.88 (s, 1H, NH), 8.67 (s, 1H), 8.45 (s, 1H), 7.92 (d, 1.7 Hz),7.76 (d, 1H, J=8.5 Hz), 7.67 (d, 1H, J=8.5 Hz), 7.50 (d, 1H, J=3.1 Hz),7.42 (d, 1H, J=8.9 Hz), 7.35 (dd, 1H, J=8.9 Hz, 1.9 Hz), 7.31-7.18 (m,6H), 6.48 (dd, 1H, J+3.1 Hz, 0.8 Hz), 5.41 (s, 2H), 2.97 (br, 2H), 2.67(br, 2H), 2.47 (s, 3H), 1.92 (br, 2H), 1.82 (br, 2H). LRMS: 488.2 (MH+),126.1.

[0321] Method G: Acetic Acid3-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-allyl Ester(27).

[0322] 3-(4-Phenoxy-quinazolin-6-yl)-acrylic acid methyl ester (24): Apressure bottle was charged with quinazoline 13 (3.5 g, 10.0 mmol),methyl acrylate (6.0 g, 70.0 mmol), Pd(OAc)₂ (140 mg, 0.62 mmol), PPh₃(320 mg, 1.22 mmol), DMF (4 mL) and NEt₃ (15 mL). The tube was purgedwith nitrogen, sealed and heated at 110° C. with stirring for 3 hours.The mixture was cooled and diluted with EtOAc and transferred to aseparatory funnel then washed with H₂O and brine and dried (MgSO₄).After filtration the filtrate was concentrated under reduced pressure toprovide a yellow solid which was recrystallized (EtOAc) to yield ester24 as a pale yellow solid (2.2 g, 72%). ¹ HNMR (CDCl₃: 400 MHz): δ 8.76(s, 1H), 8.47 (s, 1H), 8.08 (d, 1H), 8.06 (d, 1H), 7.87 (dd, J=16 Hz, 1Hz), 7.48 (t, 2H), 7.35 (t, 1H), 7.25 (m, 2H), 6.60 (d, J=16 Hz, 1 Hz),3.83 (s, 3H).

[0323] 3-(4-Phenoxy-quinazolin-6-yl)-prop-2-en-1-ol (25): To a solutionof ester 24 (1.35 g, 4.41 mmol) in toluene (60 mL) under N₂ at −78° C.was added DIBAL-H (8.8 mL of a 1M solution in toluene, 8.8 mmol)dropwise. The reaction was then warmed to 0° C. and stirred for 30minutes, then quenched with 30 mL of saturated Rochelle's salt and themixture stirred overnight. The bilayer was transferred to a separatoryfunnel and the organic layer washed with H₂O and brine and dried(MgSO₄). After filtration the organic layer was concentrated underreduced pressure to provide a yellow oil which was purified by silicagel chromatography eluting with 1:1 hexanes:EtOAc, then EtOAc. Theallylic alcohol 25 (900 mg, 73%) was isolated as a pale yellow oil. ¹HNMR (CDCl₃; 400 MHz): δ: 8.72 (s, 1H), 8.27 (s, 1H), 7.66 (m, 2H), 7.62(m, 1H), 7.47 (m, 3H), 7.34 (m, 1H), 7.24 (m, 2H), 6.82 (dd, 1 h), 6.56(m, 1H), 4.41 (dd, 1H).

[0324] Acetic acid 3-(4-phenoxy-quinazolin-6-yl)-allyl ester (26): Toalcohol 25 (900 mg, 3.23 mmol) and pyridine (0.8 mL, 10 mmol) in dryCH₂Cl₂ (15 mL) at 0° C. was added acetyl chloride (0.3 mL, 4.2 mmol).The resulting mixture was stirred for 2 hours, the diluted with CH₂Cl₂(10 mL) and 5% HCl (10 mL). The mixture was transferred to a separatoryfunnel and the organic layer washed with H₂O and brine. The organiclayer was dried (Na₂SO₄), solids filtered and the solvent removed invacuo to provide the desired acetate 26 as a yellow waxy solid (1.04 g,100%). ¹H NMR (CDCl₃; 400 MHz): 6:8.72 (s, 1H), 8.30 (d, 1H, J=1.7 Hz),7.98 (m, 2H), 7.49 (m, 2H), 7.30 (m, 1H), 7.25 (m, 2H), 6.84 (d, 1H,J=16.0 Hz), 6.46 (m, 1H), 4.79 (dd, 2H, J=6.2 Hz, 1.2 Hz), 2.11 (s, 3H).

[0325] Acetic acid3-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-allyl ester(27). A mixture of ester 26 (630 mg, 1.97 mmol) and5-amino-1-phenylsulfonylindole in phenol (3.0 g) was heated at 100° C.for 20 hours. Excess phenol was removed by distillation and theresulting brown oil was purified by silica gel chromatography elutingwith 1:1 ethyl acetate:hexanes then ethyl acetate. Quinazoline 27 (430mg, 43%) was obtained as an off-white waxy solid. ¹H NMR (CDCl₃; 400MHz): δ: 8.61 (s, 1H), 7.92 (m, 3H), 7.82 (m, 4H), 7.51 (m, 2H), 7.43(m, 3H), 6.74 (d, 1H), 6.62 (d, 1H), 6.45 (dt, 1H), 4.74 (dd, 2H), 2.09(s, 3H).

[0326] Method G′:3-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl]-acrylic acidmethyl ester (28) and3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-en-1-ol (29). Anidentical procedure to that used to transform intermediate 26 into 27was used to convert 4-phenoxyquinazoline intermediates 24 and 25 intotheir respective 4-arylaminoquinazoline derivatives 28 and 29respectively.

[0327] Method H:{6-[3-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-yl)-propenyl]-quinazolin-4-yl}-(1-benzenesulfonyl-1H-indol-5-yl)-amine(30).

[0328] A mixture of palladium acetate (6 mg, 0.027 mmol) andP(C₆H₄-m-SO₃Na)₃ (30 mg, 0.053 mmol) in water (0.3 mL) was stirred atroom temperature for 1 hour, followed by the addition of allylic acetate16 (150 mg, 0.30 mmol) and(1a,5a,6a)-6-t-butyloxycarbonylamino-3-azabicyclo[3.1.0]hexane (preparedas in Brighty, et. al. Synlett 1996, pp.1097-1099.) (71 mg, 0.36 mmol)in CH₃CN (3 mL). The resulting reaction mixture was stirred at 50° C.for 1.5 hours, taken up in ethyl acetate (10 mL), and washed withaqueous NH₄Cl and water. The separated organic layer was dried overNa₂SO₄ and concentrated to provide a brown oil. Purification bypreparative TLC (ethyl acetate elution) yielded 31 mg of yellow solid.The BOC-protected product obtained was dissolved in methanol (5 mL) anddeprotected by passing HCl gas through the solution with stirring. Afterconcentration and drying under high vacuum, amine 30 was obtained as itsHCl salt (18 mg, 11%): MS m/z (MH⁺) 537.2; HPLC 4.423 min.

[0329] Method I:4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-4-olhydrochloride (32).

[0330] 4-(4-Chloro-quinazolin-6-ylethynyl)-tetrahydro-pyran-4-ol (31). Amixture of 4-ethynyl-4-hydroxytetrahydropyran (70 mg, 0.55 mmol),4-chloro-6-iodoquinqzoline (145 mg, 0.50 mmol),bis(triphenylphosphine)palladium(II) chloride (24 mg, 7 mol %), copper(I) iodide (6.6 mg, 7 mol %), and diisopropylamine (56 mg, 0.55 mmol) inanhydrous THF (5 mL) was purged with N₂ and stirred for 2 hours under N₂atmosphere. After dilution with ethyl acetate (30 mL), the mixture waswashed with aqueous NH₄C₁, H₂O, and brine, dried over Na₂SO₄, andconcentrated to give the product as yellow solid. Crystallization fromethyl acetate/hexane afforded 0.13 g (90%) of a tan solid: ¹H NMR(CD₃OD) δ 1.88 (m, 2H), 2.04 (m, 2H), 3.73 (m, 2H), 3.91 (m, 2H), 8.04(s, 1H), 8.05 (s, 1H), 8.36 (s, 1H), 9.00 (s, 1H).

[0331] 4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-4-ol hydrochloride (32). A mixture of4-(4-Chloro-quinazolin-6-ylethynyl)-tetrahydro-pyran-4-ol (43 mg, 0.15mmol) and 4-phenoxyaniline (28 mg, 0.15 mmol) in 2 mL oft-BuOH/1,2-dichloroethane (1:1) was heated at 90° C. with stirring in areaction vial for 1 hour. The reaction was cooled, diluted with CH₂Cl₂and the product was collected by filtration to provide 52 mg (73%) of 32as a yellow solid: ¹H NMR (CD₃OD) δ 1.86 (m, 2H), 2.02 (m, 2H), 3.74 (m,2H), 3.92 (m, 2H), 7.05 (m, 4H), 7.15 (t, J=7.6 Hz, 1H), 7.38 (t, J=7.6Hz, 2H), 7.69 (d, J=6.8 Hz, 2H), 7.81 (d, J=7.2 Hz, 1H), 8.07 (d, J=7.2Hz, 1H), 8.75 (s, 2H); HPLC: 6.36 min.

[0332] Method J:(3-Methoxy4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine

[0333] 4-(4-Chloro-quinazolin-6-ylethynyl)-piperidine-1-carboxylic acidtert-butyl ester: A mixture of 4-ethynyl-piperidine-1-carboxylic acidtert-butyl ester (1.12 g, 5.35 mmol), 4-chloro-6-iodoquinazoline (1.35g, 4.65 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.16 g,0.23 mmol), copper(1) iodide (0.044 g, 0.23 mmol), and diisopropylamine(0.47 g, 4.65 mmol) in anhydrous THF (20 mL) was stirred at roomtemperature under nitrogen for 2 hours. After concentration, the residuewas dissolved in CH₂Cl₂ (100 mL), washed with aqueous NH₄Cl and brine,dried over sodium sulfate, and concentrated to give the crude product asbrown oil. Purification by silica gel colunin using 20% EtOAc in hexaneafforded 1.63 g (94%) of sticky, yellow oil: ¹H NMR (CDCl₃) δ 1.45 (s,9H), 1.67-1.75 (m, 2H), 1.87-1.92 (m, 2H), 2.84 (m, 1H), 3.20-3.26 (m,2H), 3.78 (br d, 2H), 7.88 (dd, 1H), 7.97 (d, 1H), 8.26 (d, 1H), 9.00(s, 1H).

[0334](3-Methoxy-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine:A solution of4-(4-chloro-quinazolin-6-ylethynyl)-piperidine-1-carboxylic acidtert-butyl ester (131 mg, 0.304 mmol) and 3-methoxy-4-phenoxyanilinehydrochloride (77 mg, 0.306 mmol) in ^(t)BuOH/ClCH₂CH₂Cl (1.0/1.0 mL)was heated in a tightly capped reaction vial at 90° C. for 30 minutes.After cooling, the yellow mixture was diluted with MeOH and HCl gas waspassed through the mixture for 10 minutes. After stirring for 2 hours,EtOAc was added to precipitate more solid which was collected by suctionfiltration, rinsed with EtOAc, and further dried to give 105 mg (66%) ofyellow solid: ¹H NMR (CD₃OD) δ 1.93-2.02 (m, 2H), 2.18-2.24 (m, 2H),3.12-3.21 (m, 2H), 3.41-3.47 (m, 2H), 3.81 (s, 3H), 6.87 (d, 2H), 7.02(t, 1H), 7.06 (d, 1H), 7.27 (t, 2H), 7.33 (dd, 1H), 7.56 (d, 1H), 7.80(d, 1H), 8.06 (d, 1H), 8.79 (s, 1H), 8.83 (s, 1H); MS m/z (MH⁺) 451.3.

[0335] Method K:(3-Methyl4-phenoxy-phenyl)-[6-(1-propyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-amine

[0336](3-Methyl-4-phenoxy-phenyl)-[6-(1-propyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-amine:(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine(114 mg, 0.2 mmol) and propionaldehyde (116 mg, 2.0 mmol) were dissolvedin MeOH/H₂O (5/0.5 mL) and the pH was adjusted to 5 with ACOH. Thereaction was stirred at room temperature overnight and followed by theaddition of NaBH₃CN (13 mg, 0.2 mmol) over a period of 1 hour. Afterstirring for another hour, the reaction was concentrated and the residuewas partitioned between CH₂Cl₂ (30 mL) and saturated Na₂CO₃ (20 mL). Theseparated organic layer was dried over sodium sulfate and concentrated.Purification by preparative TLC using 10% MeOH in EtOAc gave the freebase product which was converted to HCl salt to yield 42 mg (38%) ofyellow solid: ¹H NMR (CD₃OD) δ 1.03 (t, 3H), 1.78-1.87 (m, 4H),2.01-2.08 (m, 2H), 2.28 (s, 3H), 2.96 (t, 1H), 3.07-3.19 (m, 3H), 3.31(br, 1H), 3.59 (d, 1H), 3.80 (d, 1H), 6.94 (m, 3H), 7.09 (t, 1H), 7.34(t, 2H), 7.53 (d, 1H), 7.63 (s, 1H), 7.80 (d, 1H), 8.05 (dd,1H), 8.73(s, 1H), 8.75 (s, 1H); MS m/z (MH⁺) 477.1.

[0337] Method K′:{6-[1-(2-Amino-ethyl)-piperidin-3-ylethynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine

[0338]{6-[1-(2-Amino-ethyl)-piperidin-3-ylethynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine:(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine(114 mg, 0.2 mmol) and tert-butyl N-(2-oxoethyl)carbamate (320 mg, 2.0mmol) were dissolved in MeOH/H₂O (5/0.5 mL) and the pH was adjusted to 5with AcOH. The reaction was stirred at room temperature overnight andfollowed by the addition of NaBH₃CN (13 mg, 0.2 mmol) over a period of 1hour. After stirring for another hour, the reaction was concentrated andthe residue was partitioned between CH₂Cl₂ (30 mL) and saturated Na₂CO₃(20 mL). The separated organic layer was dried over sodium sulfate andconcentrated. Purification by silica gel column using 5% MeOH in EtOAcgave the free base which was dissolved in MeOH. HCl gas was passedthrough the solution for 5 min and the deprotected product precipitatedas HCl salt. The mixture was diluted with EtOAc and the solid wascollected by suction filtration, rinsed with EtOAc, and further dried toafford 83 mg (71%) of yellow solid: ¹H NMR (CD₃OD) δ 1.71-1.82 (br, 2H),2.0-2.12 (br, 2H), 2.27 (s, 3H), 3.00 (t, 1H), 3.03-3.19 (br, 2H), 3.40(br, 1H), 3.50 (s, 2H), 3.62 (br d, 1H), 3.70 (m, 1H), 3.89 (br d, 1H),6.93 (m, 3H), 7.08 (t, 1H), 7.33 (t, 2H), 7.52 (d, 1H), 7.64 (s, 1H),7.79 (d, 1H), 8.05 (d, 1H), 8.75 (s, 1H), 8.77 (s, 1H); MS m/z (MH⁺)476.1.

[0339] Method L:3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol:

[0340]3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol:A mixture of3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yiethynyl]-piperidin-3-oldihydrochloride (100 mg, 0.19 mmol) and Pd/C (10%, 6 mg) was shaken in aParr bottle with hydrogen at 50 psi overnight and filtered through a padof Celite. The filtrate was concentrated to small volume and addeddropwise into EtOAc with stirring. The solid was collected by suctionfiltration, rinsed with EtOAc, and further dried to yield 89 mg (89%) ofyellow solid: ¹H NMR (CD₃OD) δ 1.69 (dt, 1H), 1.81(br d, 1H), 1.95 (t,3H), 2.15 (m, 1H), 2.28 (t, 3H), 2.93 (t, 1H), 3.02 (m, 3H), 3.18 (d,1H), 3.31(br, 1H), 6.94 (m, 3H), 7.08 (t, 1H), 7.34 (t, 2H), 7.55 (d,1H), 7.66 (d, 1H), 7.78 (d, 1H), 8.02 (d, 1H), 8.58 (s, 1H), 8.73 (s,1H); MS m/z (MH⁺) 455.2.

[0341] Method M:N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2-morpholin-4-yl-acetam

[0342] 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide:2-Chloro-N-prop-2-ynyl-acetamide (385 mg; 2.93 mmol) and4-chloro-6-iodoquinazoline (850 mg; 1 equiv.) were dissolved in dry THFand diisopropylamine (296 mg; 0.41 ml; 1 equiv.). To this mixture wasadded 0.04 equivalents of copper iodide (22 mg) and Pd(PPh₃)₂Cl₂ (82mg). The reaction was stirred at room temperature under a nitrogenatmosphere overnight (−20 hrs). The solvent was then removed in vacuoand the residue dissolved in CH₂Cl₂. This solution was transferred to aseparatory funnel and washed with 1×saturated NH₄Cl, brine, dried overNa₂SO₄ and the solvent removed in vacuo. The product was purified bysilica gel chromatography eluting with 1:1 hex/EtOAc and collectingfractions with an Rf=0.25. This yielded the2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide as anoff white solid (454 mg; 53%). ¹H NMR (400 MHz; CDCl₃) δ 4.12 (2H, s),4.40 (2H, d, J=5.2 Hz), 7.91-7.93 (1H, dd, J=2, 6.8 Hz), 8.00 (1H, d,J=8.4 Hz), 8.34 (1H, d, J=1.6 Hz), 9.03 (1H, s). Irms (M+): 294.0,296.0, 298.1.

[0343]2-Chloro-N-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide:A solution of2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide (50 mg;0.17 mmol) and 3-methyl-4-phenoxyaniline (36 mg; 0.9 equiv.) in1,2-dichloroethane (1 ml) and t-butanol (1 ml) was heated at 87° C. for30 minutes. The mixture was then cooled to room temperature and dilutedwith ethyl acetate to further facilitate precipitation. The solution wasthen filtered to give the coupled product as a yellow powder (73 mg;90%). 2.28 (3H, s), 4.10 (2H, s), 4.30 (2H, s), 6.93 (3H, d), 7.09 (1H,t), 7.34 (2H, t), 7.50-7.53 (1H, dd, J=2.6, 6 Hz), 7.63 (1H, d, J=2.4Hz), 7.78 (1H, d, J=8 Hz), 8.06-8.08 (1H, dd, J=1.4, 7.2 Hz), 8.68 (1H,d, J=1.2 Hz), 8.75 (1H, s). Irms(M+): 457.0, 4.59.1; (M-): 455.7, 419.6

[0344]N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2-morpholin-4-yl-acetamide:To a solution of2-Chloro-N-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide(63 mg; 0.12 mmol) in toluene (10 ml) was added 3 equivalents ofmorpholine (31 mg) and the mixture heated at reflux overnight. Thereaction was cooled to room temperature and the morpholine salts werefiltered out and the solvent removed from the filtrate. The residue wasredissolved in CH₂Cl₂ with a small amount of methanol and HCl gas wasbubbled through the solution for 2-3 minutes. The solution was thenconcentrated to 2-3 ml, diluted with ethyl acetate and filtered toobtainN-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2-morpholin-4-yl-acetamideas a yellow/brown solid (65 mg; 94%). ¹H NMR (400 MHz; CD₃OD) δ 2.27(3H, s), 3.21 (2H, m), 3.56 (2H, m), 3.87 (2H, m), 4.04 (2H, m), 4.09(2H, s), 4.36 (2H, s), 6.93 (3H, d, J=8.4), 7.09 (1H, t, J=7.4 Hz), 7.34(2H, t, J=8 Hz), 7.54 (1H, dd), 7.65 (1H, s), 7.82 (1H, d, J=8.8 Hz),8.06 (1H, d, J=8.4 Hz), 8.76 (1H, s), 8.80 (1H, s). Irms(M+): 508.0;(M−): 506.0.

[0345] Method N:(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-pyrido[3,4-d]pyrimidin-4-yl)-amine

[0346] 4,6-Dichloro-pyrido[3,4-d]pyrimidine: DMF (0.1 ml) was added to6-chloro-3H-pyrido[3,4-d]pyrimidin-4-one (1.82 g, 10 mmol) followed bydropwise addition of thionyl chloride (10 ml). The flask was fitted witha condenser and a drying tube and the contents heated to reflux for ˜20minutes whereupon the solids dissolved. The heating was continued for afurther 1 h and then cooled. Toluene was added to wash the sides of theflask and the solvents were evaporated in vacuo. Azeotroping withtoluene was repeated twice and the crude so obtained was taken throughto the next step.

[0347](6-Chloro-pyrido[3,4-d]pyrimidin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine:The 4,6-dichloro-pyrido[3,4-d]pyrimidine obtained from the previousreaction was taken up in dioxane (50 ml), the 3-methyl 4-phenoxy anilinehydrochloride (2.8 g, 12 mmol) was added and the contents heated to anexternal bath temperature of ˜80° C. for 3 hours, whereupon yellowprecipitation occurred. Further dioxane (20 ml) was added and thecontents heated at ˜75° C. for 12 hours. The solution was then filteredand the yellow solid placed under vacuum to provide the desired(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-(3-methyl-4-phenoxy-phenyl)-aminehydrochloride (3.6 g, ˜100%). ¹H NMR (CD₃OD; 400 MHz) δ 9.05 (s, 1H),8.87 (s, 1H), 8.64 (s, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.58 (dd, J=8.7, 2.5Hz, 1H), 7.35 (dd, J=8.7, 7.5 Hz, 2H), 7.10 (t, J=7.2 Hz, 1H), 6.94 (d,J=8.7 Hz, 3H), 2.29 (s, 3H). MS m/z (MH⁺): 363.2

[0348](3-Methyl-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-pyrido[3,4-d]pyrimidin4-yl)-amine:A flame dried pear shaped flask was charged with the(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-(3-methyl-4-phenoxy-phenyl)-aminehydrochloride (200 mg, 0.5 mmol), the 4-ethynyl-piperidine-1-carboxylicacid tert-butyl ester (314 mg, 1.5 mmol), Pd(PhCN)₂Cl₂ (19 mg, 0.05mmol), 1,4-bis (diphenylphosphino)butane (32 mg, 0.075 mmol) and CuI(4.8 mg, 0.025 mmol). Dioxane (5 ml) was added and to this stirredsuspension under Ar was added diisopropylamine (0.32 ml, 2.28 mmol)whereupon a lot of the solid dissolved. The flask (fitted with acondenser) was then placed in a preheated oil-bath and heated at a bathtemperature of 104° C. for 14 hours at which point LC/MS indicateddisappearance of starting material. The reaction mixture was thenfiltered through a plug of silica, concentrated and chromatographedusing a gradient elution of 20-80% EtOAc-hexanes to give the desiredcoupled product as a solid (165 mg, 62%). The solid was taken up inCH₂Cl₂ (and sparing amounts of MeOH to help in dissolution), HCl (g) wasbubbled through, followed by addtition of ether whereupon solidprecipiated out which was filtered and placed under vacuo to give thedesired(3-methyl-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-pyrido[3,4-d]pyrimidin-4-yl)-amineas a dihydrochloride salt. ¹H NMR (CDCl₃; 400 MHz) δ 9.12 (s, 1H),8.85(s, 1H), 8.68 (s, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.58 (dd, J=8.7, 2.5Hz, 1H),7.34 (dd, J=8.3, 7.5 Hz, 2H), 7.10 (app t, J=7.2 Hz, 1H), 6.94(d, J=8.7 Hz, 3H), 3.42 (m, 2H), 3.19 (m, 3H), 2.29 (s, 3H), 2.22 (m,2H), 2.0 (m, 2H). MS m/z (MH⁺): 436.3.

[0349] Method O:4-Amino-4-methyl-1-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol

[0350]5-(4-Chloro-quinazolin-6-ylethynyl)-4,4-dimethyl-oxazolidin-2-one: Amixture of 4,4-Dimethyl-5-ethynyl-2-oxazolidinone (1.10 g, 7.90 mmol),4-chloro-6-iodoquinazoline (1.63 g, 5.60 mmol),dichlorobis(triphenylphosphine)palladium(II) (200 mg, 0.28 mmol), copperiodide (53 mg, 0.28 mmol), and diisopropylamine (0.57 g, 5.60 mmol) inanhydrous THF (30 mL) was stirred at room temperature under nitrogen for4 hours. After concentration, the residue was dissolved in CH₂Cl₂ (80mL), washed with aqueous NH₄Cl and brine, dried over sodium sulfate, andconcentrated to give the crude product as brown oil. Purification bysilica gel column using 50-70% EtOAc in hexane afforded 1.22 g (72%) ofyellow solid: ¹H NMR (CDCl₃) δ 1.49 (s, 3H), 1.53 (s, 3H), 5.14 (s, 1H),5.57 (br s, 1H), 7.95 (dd, 1H), 8.04 (d, 1H, J=8.8 Hz), 8.38 (d, 1H,J=2.0 Hz), 9.05 (s, 1H).

[0351]4-Amino-4-methyl-1-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol:A solution of5-(4-Chloro-quinazolin-6-ylethynyl)-4,4-dimethyl-oxazolidin-2-one (151mg, 0.5 mmol) and 3-methyl-4-phenoxyaniline hydrochloride (130 mg, 0.55mmol) in ^(t)BuOH/ClCH₂CH₂Cl (1:1, 2.0 mL) was heated in a tightlycapped reaction vial at 90° C. for 30 minutes. After cooling, the yellowmixture was diluted with EtOAc to precipitate more solid which wascollected by suction filtration, rinsed with EtOAc, and further dried togive 215 mg (86%) of yellow solid. This material (215 mg, 0.43 mmol) wasimmediately combined with KOH (0.51 g, 9.0 mmol) in MeOH/H₂O (9/3 mL)and refluxed for 20 hours. After cooling, the reaction was neutralizedwith 0.60 g (10.0 mmol) of AcOH and concentrated. The residue wassuspended in CH₂Cl₂ and purified on a silica gel column using 20% MeOHin CH₂Cl₂. The purified free base was converted to HCl salt to afford 46mg (22%) of yellow solid: ¹H NMR (CD₃OD) δ 1.49 (s, 3H), 1.52 (s, 3H),2.28 (s, 3H), 4.64 (s, 1H), 6.93 (m, 3H), 7.09 (t, 1H), 7.34 (m, 2H),7.55 (dd, 1H), 7.65 (d, 1H), 7.83 (d, 1H), 8.13 (dd, 1H), 8.77 (s, 1H),8.87 (s, 1H); MS m/z (MH⁺) 439.2.

[0352] The following examples were prepared using the methods describedabove. In the Table below, the term “min” refers to minutes. Examplenumbers in the following table do not correspond to compound numbersreferred to in the preceding experimental section. TABLE HPLC MethodRetention to LRMS time Example Prepare IUPAC name (MH+) (min)  1 I2-Methyl-4-[4-(4-phenoxy- 396.1 6.88 phenylamino)-quinazolin-6-yl]-but-3-yn-2-ol  2 G′ 3-[4-(4-Phenoxy-phenylamino)- 370.1 6.06quinazolin-6-yl]-(E)-prop-2-en-1-ol  3 B(6-Cyclobutyl-quinazolin-4-yl)-(4- 368.2 8.35 phenoxy-phenyl)-amine  4 B(6-Cyclopropyl-quinazolin-4-yl)-(4- 354.2 7.62 phenoxy-phenyl)-amine  5I 1-Methoxy-2-methyl-4-[4-(4-phenoxy- 426.1 6.66phenylamino)-quinazolin-6-yl]-but- 3-yn-2-ol  6 I4-[4-(4-Phenoxy-phenylamino)- 459.0 6.56quinazolin-6-yl]-2-pyridin-4-yl-but-3- yn-2-ol  7 I1-[4-(4-Phenoxy-phenylamino)- 436.1 7.80quinazolin-6-ylethynyl]-cyclohexanol  8 G N-Methyl-3-[4-(4-phenoxy-397.2 5.81 phenylamino)-quinazolin-6-yl]- acrylamide  9 G′3-[4-(4-Benzyl-phenylamino)- 368.2 6.20quinazolin-6-yl]-(E)-prop-2-en-1-ol  10 G′N,N-Diethyl-3-[6-(3-hydroxy-(E)- 377.2 4.28propenyl)-quinazolin-4-ylamino]- benzamide  11 I4-[4-(4-Benzyloxy-phenylamino)- 465.1 4.88quinazolin-6-ylethynyl]-1-methyl- piperidin-4-ol  12 I4-[4-(1-Benzenesulfonyl-1H-indol-5- 538.2, 4.86 ylamino)-quinazolin-6-445.0 ylethynyl]-1-methyl-piperidin-4-ol  13 I4-[4-(4-Benzyl-phenylamino)- 449.2, 5.11quinazolin-6-ylethynyl]-1-methyl- 356.2 piperidin-4-ol  14 I1-Methyl-4-[4-(4-phenoxy- 451.2, 4.89phenylamino)-quinazolin-6-ylethynyl]- 143.2 piperidin-4-ol  15 B3-(6-Cyclobutyl-quinazolin-4-ylamino)- 375.3 6.24 N,N-diethyl-benzamide 16 B (4-Benzyl-phenyl)-(6-cyclobutyl- 366.3 8.49 quinazolin-4-yl)-amine 17 B (6-Cyclobutyl-quinazolin-4-yl)-(1H- 315.3 5.63 indol-5-yl)-amine 18 B (4-Benzyloxy-phenyl)-(6-cyclobutyl- 382.2 7.98quinazolin-4-yl)-amine  19 G′ 3-[4-(1H-Indol-5-ylamino)-quinazolin-317.3 3.66 6-yl]-(E)-prop-2-en-1-ol  20 G′3-[4-(4-Benzyloxy-phenylamino)- 384.3 5.85quinazolin-6-yl]-(E)-prop-2-en-1-ol  21 I 4-[4-(4-Phenoxy-phenylamino)-438.1 6.34 quinazolin-6-ylethynyl]-tetrahydro- pyran-4-ol  22 I4-[4-(1-Benzenesulfonyl-1H-indol-5- 483.2 6.55ylamino)-quinazolin-6-yl]-2- methyl-but-3-yn-2-ol  23 I4-[4-(1H-Indol-5-ylamino)-quinazolin- 343.2 4.616-yl]-2-methyl-but-3-yn-2-ol  24 I 4-[4-(4-Benzyl-phenylamino)- 394.27.06 quinazolin-6-yl]-2-methyl-but-3-yn-2-ol  25 C3-[4-(4-Phenoxy-phenylamino)- 440.2 7.93/quinazolin-6-yl]-cyclobutanecarboxylic 7.83 acid ethyl ester  26 B(1-Benzenesulfonyl-1H-indol-5-yl)-(6- 455.2 7.80cyclobutyl-quinazolin-4-yl)-amine  27 I 4-[4-(4-Phenoxy-phenylamino)-459.2 6.64 quinazolin-6-yl]-2-pyridin-3-yl-but-3- yn-2-ol  28 I4-[4-(1-Benzenesulfonyl-1H-indol-5- 546.2 6.27ylamino)-quinazolin-6-yl]-2-pyridin-3- yl-but-3-yn-2-ol  29 G′3-[4-(1-Benzenesulfonyl-1H-indol-5- 457.2 5.80ylamino)-quinazolin-6-yl]-(E)-prop-2-en-1-ol  30 G′3-[4-(1-Benzyl-1H-indol-5-ylamino)- 407.3 5.72quinazolin-6-yl]-(E)-prop-2-en-1-ol  31 G′3-[4-(1-Benzyl-1H-indazol-5-ylamino)- 408.2 5.15quinazolin-6-yl]-(E)-prop-2-en-1-ol  32 I4-[4-(1-Benzyl-1H-indol-5-ylamino)- 488.2 4.84quinazolin-6-ylethynyl]-1-methyl- piperidin-4-ol  33 I4-[4-(4-Benzyl-phenylamino)- 525.1 6.11quinazolin-6-ylethynyl]-tetrahydro- pyran-4-ol  34 I4-[4-(1-Benzenesulfonyl-1H-indol-5- 436.2 6.56ylamino)-quinazolin-6-ylethynyl]- tetrahydro-pyran-4-ol  35 A(1-Benzenesulfonyl-1H-indol-5-yl)-[6- 505.2 5.80(3-imidazol-1-yl-prop-1-ynyl)- quinazolin-4-yl]-amine  36 I5-Methoxy-3,5-dimethyl-1-[4-(4- 468.3 8.01phenoxy-phenylamino)-quinazolin-6- yl]-hex-1-yn-3-ol  37 I1-[4-(4-Benzyl-phenylamino)- 466.3 8.21 quinazolin-6-yl]-5-methoxy-3,5-dimethyl-hex-1-yn-3-ol  38 I 1-[4-(1-Benzenesulfonyl-1H-indol-5- 555.27.55 ylamino)-quinazolin-6-yl]-5- methoxy-3,5-dimethyl-hex-1-yn-3-ol  39I 4-[4-(4-Benzyl-phenylamino)- 457.4 6.79quinazolin-6-yl]-2-pyridin-3-yl-but-3- yn-2-ol  40 I4-[4-(4-Benzyl-phenylamino)- 457.3 6.71quinazolin-6-yl]-2-pyridin-4-yl-but-3-yn-2-ol  41 A(1-Benzenesulfonyl-1H-indol-5-yl)-[6- 482.2 5.16(3-dimethylamino-prop-1-ynyl)- quinazolin-4-yl]-amine  42 G Acetic acid3-[4-(1-benzenesulfonyl- 499.2 7.011H-indol-5-ylamino)-quinazolin-6-yl]- (E)-allyl ester  43 C3-[4-(1-Benzenesulfonyl-1H-indol-5- 527.2 7.54/7.64ylamino)-quinazolin-6-yl]- cyclobutanecarboxylic acid ethyl ester  44 I1-Methyl-4-{4-[1-(propane-2-sulfonyl)- 504.3 4.411H-indol-5-ylamino]-quinazolin-6- ylethynyl}-piperidin-4-ol  45 H{6-[3-(6-Amino-3-aza- 537.2 4.42 bicyclo[3.1.0]hex-3-yl(1a,5a,6a))-propenyl]-quinazolin-4-yl}-(1- benzenesulfonyl-1H-indol-5-yl)-amine  46I 2-Methyl-4-{4-[1-(propane-2-sulfonyl)- 449.2 6.111H-indol-5-ylamino]-quinazolin-6-yl}- but-3-yn-2-ol  47 I4-[4-(4-Benzyloxy-phenylamino)- 410.3 6.63quinazolin-6-yl]-2-methyl-but-3-yn-2-ol  48 IN,N-Diethyl-3-[6-(3-hydroxy-3-methyl- 403.3 5.06but-1-ynyl)-quinazolin-4-ylamino]- benzamide  49 I4-[4-(1-Benzenesulfonyl-1H-indol-5- 546.3 6.26ylamino)-quinazolin-6-yl]-2pyridin-4- yl-but-3-yn-2-ol  50 D{3-[4-(1-Benzenesulfonyl-1H-indol-5- 485.2 5.97ylamino)-quinazolin-6-yl]-cyclobutyl}- methanol  51 A(1-Benzenesulfonyl-1H-indol-5-yl)-{6- 512.2 5.11[3-(2-methoxy-ethylamino)-prop-1- ynyl]-quinazolin-4-yl}-amine  52 A(1-Benzenesulfonyl-1H-indol-5-yl)-{6- 563.2 5.23[3-(2-piperidin-1-yl-ethylamino)-prop- 1-ynyl]-quinazolin-4-yl}-amine 53 E {3-(4-(1-Benzenesulfonyl-1H-indol-5- 552.2 6.45/6.64ylamino)-quinazolin-6-yl]-cyclobutyl}- pyrrolidin-1-yl-methanone  54 A(1-Benzenesulfonyl-1H-indol-5-yl)-[6- 524.2 6.45(3-morpholin-4-yl-prop-1-ynyl)- quinazolin-4-yl]-amine  55 A(1-Benzenesulfonyl-1H-indol-5-yl)-{6- 572.2 6.36[3-(1,1-dioxo-1&-thiomorpholin-4-yl)-prop-1-ynyl]-quinazolin-4-yl}-amine  56 A(1-Benzenesulfonyl-1H-indol-5-yl)-[6- 468.2 4.89(3-methylamino-prop-1-ynyl)- quinazolin-4-yl]-amine  57 A(1-Benzenesulfonyl-1H-indol-5-yl)-{6- 567.2 5.05[3-(2-morpholin-4-yl-ethylamino)-prop- 1-ynyl]-quinazolin-4-yl}-amine 58 A (1-Benzenesulfonyl-1H-indol-5-yl)-(6- 594.2 4.41{3-[3-(4-methyl-piperazin-1-yl)- propylamino]-prop-1-ynyl}-quinazolin-4-yl)-amine  59 A (1-Benzenesulfonyl-1H-indol-5-yl)-[6- 508.3 5.21(3-pyrrolidin-1-yl-prop-1-ynyl)- quinazolin-4-yl]amine  60 I4-[4-(1-Benzyl-1H-indazol-5-ylamino)- 476.2 5.55quinazolin-6-ylethynyl]-tetrahydro- pyran-4-ol  61 I4-[4-(1-Benzyl-1H-indol-5-ylamino)- 475.2 6.16quinazolin-6-ylethynyl]-tetrahydro- pyran-4-ol  62 I4-[4-(1-Cyclopropylmethyl-1H-indol-5- 439.3 5.82ylamino)-quinazolin-ylethynyl]- tetrahydro-pyran-4-ol  63 I4-[4-(1-Ethanesulfonyl-1H-indol-5- 477.2 5.34ylamino)-quinazolin-6-ylethynyl]- tetrahydro-pyran-4-ol  64 I4-[4-(1-Methanesulfonyl-1H-indol-5- 463.2 4.99ylamino)-quinazolin-6-ylethynyl]- tetrahydro-pyran-4-ol  65 G′3-[4-(1-Benzyl-1H-indazol-5-ylamino)- 436.2 6.59quinazolin-6-yl]-(E)-acrylic acid methyl ester  66 I1-[4-(1-Benzyl-1H-indol-5-ylamino)- 473.3 7.51quinazolin-6-ylethynyl]-cyclohexanol  67 I1-[4-(1-Benzenesulfonyl-1H-indol-5- 523.3 7.37ylamino)-quinazolin-6-ylethynyl]- cyclohexanol  68 I4-[4-(1-Benzenesulfonyl-1H-indol-5- 513.3 6.37ylamino)-quinazolin-6-yl]-1- methoxy-2-methyl-but-3-yn-2-ol  69 I4-[4-(1-Benzyl-1H-indol-5-ylamino)- 463.3 6.43quinazolin-6-yl]-1-methoxy-2- methyl-but-3-yn-2-ol  70 I4-[4-(1-Benzyl-1H-indol-5-ylamino)- 496.2 6.38quinazolin-6-yl]-2-pyridin-3-yl- but-3-yn-2-ol  71 J4-[4-(1-Benzenesulfonyl-1H-indol-5- 524.2 4.78 ylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol  72 J (1-Benzenesulfonyl-1H-indol-5-yl)-(6-508.1 5.67 piperidin-4-ylethynyl- quinazolin-4-yl)-amine  73 J[6-(4-Amino-tetrahydro-pyran-4- 524.3 5.00ylethynyl)-quinazolin-4-yl]-(1- benzenesulfonyl-1H-indol-5-yl)-amine  74I 4-[4-(4-Benzyloxy-phenylamino)- 452.3 6.26quinazolin-6-ylethynyl]-tetrahydro- pyran-4-ol  75 I4-{4-[3-Methyl-4-(pyridin-2- 467.3 5.24ylmethoxy)-phenylamino]-quinazolin- 6-ylethynyl}-tetrahydro-pyran-4-ol 76 I 1-Methyl-4-{4-[3-methyl-4-(pyridin-2- 480.3 4.07ylmethoxy)-phenylamino]- quinazolin-6-ylethynyl}-piperidin-4-ol  77 J3-[4-(1-Benzenesulfonyl-1H-indol-5- 524.2 5.6ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol  78 I1-Cyclopropyl-3-{4-[1-(propane-2- 461.1 6.23sulfonyl)-1H-indol-5-ylamino]- quinazolin-6-yl}-prop-2-yn-1-ol  79 I1-Cyclopropyl-3-[4-(4-phenoxy- 408.2 7.00phenylamino)-quinazolin-6-yl]-prop-2-yn-1-ol  80 I4-Methyl-1-[4-(4-phenoxy- 410.3 7.48phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol  81 I1-[4-(1-Benzenesulfonyl-1H-indol-5- 497.2 7.09ylamino)-quinazolin-6-yl]-4-methyl- pent-1-yn-3-ol  82 I1-[4-(1-Benzyl-1H-indazol-5-ylamino)- 448.3 6.58quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol  83 I4-Methyl-1-{4-[1-(propane-2-sulfonyl)- 463.2 6.691H-indol-5-ylamino]-quinazolin-6-yl}- pent-1-yn-3-ol  84 I1-[4-(4-Benzyloxy-phenylamino)- 424.2 7.31quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol  85 I4-[4-(4-Phenoxy-phenylamino)- 437.2 4.81quinazolin-6-ylethynyl]-piperidin-4-ol  86 I 4-{4-[4-(1-Phenyl-ethoxy)-466.2 6.46 phenylamino]-quinazolin-6-ylethynyl}- tetrahydro-pyran-4-ol 87 I 1-[4-(1-Benzyl-1H-indazol-5-ylamino)- 462.3 7.00quinazolin-6-yl]-4,4-dimethyl-pent-1-yn-3-ol  88 I4,4-Dimethyl-1-[4-(4-phenoxy- 424.2 7.89phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol  89 I4,4-Dimethyl-1-{4-[1-(propane-2- 477.2 7.12sulfonyl)-1H-indol-5-ylamino]- quinazolin-6-yl}-pent-1-yn-3-ol  90 I1-[4-(1-Benzenesulfonyl-1H-indol-5- 511.2 7.51ylamino)-quinazolin-6-yl]-4,4- dimethyl-pent-1-yn-3-ol  91 I1-[4-(4-Benzyloxy-phenylamino)- 438.2 7.74quinazolin-6-yl]-4,4-dimethyl-pent-1-yn-3-ol  92 I4,4-Dimethyl-1-{4-[4-(1-phenyl- 452.3 7.95ethoxy)-phenylamino]-quinazolin-6- yl}-pent-1-yn-3-ol  93 J3-[4-(1-Benzyl-1H-indazol-5-ylamino)- 475.2 4.42quinazolin-6-ylethynyl]-piperidin-3-ol  94 JN,N-Diethyl-3-[6-(3-hydroxy-piperidin- 444.3 3.743-ylethynyl)-quinazolin-4-ylamino]- benzamide  95 J3-[4-(4-Phenoxy-phenylamino)- 437.2 4.97quinazolin-6-ylethynyl]-piperidin-3-ol  96 J3-[4-(4-Benzyloxy-phenylamino)- 451.3 4.94quinazolin-6-ylethynyl]-piperidin-3-ol  97 J 3-[4-(3-Chloro-4-phenoxy-471.2 5.38 phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol  98 J3-[4-(4-Benzyl-phenylamino)- 435.2 5.16quinazolin-6-ylethynyl]-piperidin-3-ol  99 J3-[4-(1H-Indol-5-ylamino)-quinazolin- 384.2 3.226-ylethynyl]-piperidin-3-ol 100 I 3-[4-(1-Benzenesulfonyl-1H-indol-5-509.1 7.21 ylamino)-quinazolin-6-yl]-1- cyclobutyl-prop-2-yn-1-ol 101 I1-Cyclobutyl-3-{4-[1-(propane-2- 475.2 6.81sulfonyl)-1H-indol-5-ylamino]- quinazolin-6-yl}-prop-2-yn-1-ol 102 I3-[4-(3-Chloro-4-phenoxy- 456.2 8.11 phenylamino)-quinazolin-6-yl]-1-cyclobutyl-prop-2-yn-1-ol 103 I 1-Cyclobutyl-3-[4-(3-methyl-4- 436.27.95 phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-yn-1-ol 104 I3-[4-(1-Benzyl-1H-indazol-5-ylamino)- 460.2 6.69quinazolan-6-yl]-1-cyclobutyl-prop-2- yn-1-ol 105 I1-Cyclobutyl-3-[4-(4-phenoxy- 422.2 7.59phenylamino)-quinazolin-6-yl]-prop-2- yn-1-ol 106 J3-[4-(3-Methyl-4-phenoxy- 451.2 5.26 phenylamino)-quinazolin-6-yl]-1-pyrrolidin-2-yl-prop-2-yn-1-ol 107 I 3-[4-(1-Benzenesulfonyl-1H-indol-5-538.2 4.92 ylamino)-quinazolin-6-ylethynyl]-1- methyl-piperidin-3-ol 108J 3-[4-(3-Methyl-4-phenoxy- 437.2 5.08phenylamino)-quinazolin-6-ylethynyl]- pyrrolidin-3-ol 109 J3-[4-(1-Benzyl-1H-indol-5-ylamino)- 474.2 5.00quinazolin-6-yl]-1-pyrrolidin-2-yl-prop- 2-yn-1-ol 110 I5-[4-(4-Benzyl-phenylamino)- 449.2 7.03quinazolin-6-ylethynyl]-4,4-dimethyl- oxazolidin-2-one 111 I4,4-Dimethyl-5-[4-(3-methyl-4- 465.2 7.17phenoxy-phenylamino)-quinazolin-6- ylethynyl]-oxazolidin-2-one 112 I5-[4-(3-Chloro-4-phenoxy- 485.1 7.34phenylamino)-quinazolin-6-ylethynyl]- 4,4-dimethyl-oxazolidin-2-one 113I 5-[4-(1-Benzyl-1H-indazol-5-ylamino)- 489.2 6.00quinazolin-6-ylethynyl]-4,4-dimethyl- oxazolidin-2-one 114 I5-[4-(1-Benzyl-1H-indol-5-ylamino)- 488.2 6.58quinazolin-6-ylethynyl]-4,4-dimethyl- oxazolidin-2-one 115 I5-[4-(1-Benzenesulfonyl-1H-indol-5- 538.1 6.21ylamino)-quinazolin-6-ylethynyl]-4,4- dimethyl-oxazolidin-2-one 116 J3-[4-(3-Chloro-4-phenoxy- 457.1 5.27phenylamino)-quinazolin-6-ylethynyl]- pyrrolidin-3-ol 117 J3-[4-(1-Benzyl-1H-indazol-5-ylamino)- 461.2 4.31quinazolin-6-ylethynyl]-pyrrolidin-3-ol 118 J3-{4-[1-(Propane-2-sulfonyl)-1H-indol- 476.1 4.355-ylamino]-quinazolin-6-ylethynyl}- pyrrolidin-3-ol 119 J3-[4-(3-Benzyloxy-phenylamino)- 437.2 4.85quinazolin-6-ylethynyl]-pyrrolidin-3-ol 120 J3-[4-(3-Phenoxy-phenylamino)- 423.2 4.87quinazolin-6-ylethynyl]-pyrrolidin-3-ol 121 J3-[4-(1-Benzyl-1H-indol-5-ylamino)- 460.0 4.81quinazolin-6-ylethynyl]-pyrrolidin-3-ol 123 J3-[4-(1-Benzenesulfonyl-1H-indol-5- 510.2 4.82ylamino)-quinazolin-6-ylethynyl]- pyrrolidin-3-ol 124 J3-[4-(1-Benzyl-1H-indol-5-ylamino)- 474.2 4.92quinazolin-6-ylethynyl]-piperidin-3-ol 125 J3-{4-[3-Methyl-4-(pyridin-2- 466.2 4.14ylmethoxy)-phenylamino]-quinazolin- 6-ylethynyl}-piperidin-3-ol 126 J3-{4-[1-(Propane-2-sulfonyl)-1H-indol- 490.1 4.465-ylamino]-quinazolin-6-ylethynyl}- piperidin-3-ol 127 J3-[4-(4-Phenoxy-phenylamino)- 437.2 5.08quinazolin-6-yl]-1-pyrrolidin-2-yl-prop- 2-yn-1-ol 128 J3-[4-(1-Benzyl-1H-indazol-5-ylamino)- 475.2 4.45quinazolin-6-yl]-1-pyrrolidin-2-yl-prop- 2-yn-1-ol 129 J3-{4-[1-(Propane-2-sulfonyl)-1H-indol- 490.2 4.525-ylamino]-quinazolin-6-yl}-1- pyrrolidin-2-yl-prop-2-yn-1-ol 130 J3-[4-(4-Benzyloxy-phenylamino)- 451.2 4.99quinazolin-6-yl]-1-pyrrolidin-2-yl-prop- 2-yn-1-ol 131 J3-[4-(1-Benzenesulfonyl-1H-indol-5- 524.2 4.94ylamino)-quinazolin-6-yl]-1-pyrrolidin- 2-yl-prop-2-yn-1-ol 132 O4-Amino-1-[4-(3-chloro-4-phenoxy- 459.1 5.41phenylamino)-quinazolin-6-yl]-4- methyl-pent-1-yn-3-ol 133 J3-[4-(3-Fluoro-4-phenoxy- 455.2 5.19phenylamino)-quinazolin-6-ylethynyl- piperidin-3-ol 134 J3-[4-(4-Phenoxy-3-trifluoromethyl- 505.1 5.61phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 135 J4-Amino-1-[4-(1-benzenesulfonyl-1H- 498.1 4.82indol-5-ylamino)-quinazolin-6-yl]-pent- 1-yn-3-ol 136 J3-{4-[4-(3-Methoxy-phenoxy)-3- 481.2 5.15methyl-phenylamino]-quinazolin-6- ylethynyl}-piperidin-3-ol 137 J3-[4-(3-Methyl-4-m-tolyloxy- 465.1 5.56phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 138 J3-{4-[4-(2-Methoxy-phenoxy)-3- 481.1 4.94methyl-phenylamino]-quinazolin-6- ylethynyl}-piperidin-3-ol 139 J3-[4-(3-Methyl-4-o-tolyloxy- 465.2 5.50phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 140 L3-{2-[4-(3-Methyl-4-phenoxy- 455.2 4.93phenylamino)-quinazolin-6-yl]-ethyl}- piperidin-3-ol 141 J3-{4-[3-Chloro-4-(pyridin-2- 486.0 4.38ylmethoxy)-phenylamino]-quinazolin- 6-ylethynyl}-piperidin-3-ol 142 J3-[4-(5-Methyl-6-phenoxy-pyridin-3- 452.0 4.70ylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 143 L3-{2-[4-(4-Benzyl-phenylamino)- 439.2 4.81quinazolin-6-yl]-ethyl}-piperidin-3-ol 144 I 5-{4-(3-Methoxy-4-phenoxy-481.2 6.64 phenylamino)-quinazolin-6-ylethynyl]-4,4-dimethyl-oxazolidin-2-one 145 I 1-Methyl-3-[4-(3-methyl-4-phenoxy-465.2 5.34 phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 146 L3-{2-[4-(1H-Indol-5-ylamino)- 388.3 2.86quinazolin-6-yl]-ethyl}-piperidin-3-ol 147 I 3-[4-(3-Methoxy-4-phenoxy-481.1 4.96 phenylamino)-quinazolin-6-ylethynyl]- 1-methyl-piperidin-3-ol148 I 3-[4-(3-Chloro-4-phenoxy- 485.1 5.48phenylamino)-quinazolin-6-ylethynyl]- 1-methyl-piperidin-3-ol 149 JEndo-α-3-[4-(3-Chloro-4-phenoxy- 497.1 5.47phenylamino)-quinazolin-6-ylethynyl]- 8-aza-bicyclo[3.2.1]octan-3-ol 150J Endo-α-3-[4-(3-Methoxy-4-phenoxy- 493.2 4.95phenylamino)-quinazolin-6-ylethynyl]- 8-aza-bicyclo[3.2.1]octan-3-ol 151J Endo-α-3-[4-(3-Methyl-4-phenoxy- 477.2 5.29phenylamino)-quinazolin-6-ylethynyl]- 8-aza-bicyclo[3.2.1]octan-3-ol 152J Exo-β-3-[4-(3-Chloro-4-phenoxy- 497.1 5.35phenylamino)-quinazolin-6-ylethynyl]- 8-aza-bicyclo[3.2.1]octan-3-ol 153J Exo-β-3-[4-(3-Methoxy-4-phenoxy- 493.2 4.86phenylamino)-quinazolin-6-ylethynyl]- 8-aza-bicyclo[3.2.1]octan-3-ol 154J Exo-β-3-[4-(3-Methyl-4-phenoxy- 477.2 5.21phenylamino)-quinazolin-6-ylethynyl]- 8-aza-bicyclo[3.2.1]octan-3-ol 155J Exo-β-3-[4-(4-Phenoxy- 463.2 4.96phenylamino)-quinazolin-6-ylethynyl]- 8-aza-bicyclo[3.2.1]octan-3-ol 156J (−)-3-[4-(3-Methyl-4-phenoxy- 451.2 5.22phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 157 J(+)-3-[4-(3-Methyl-4-phenoxy- 451.2 5.22phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 158 JEndo-α-3-[4-(4-Phenoxy- 463.2 5.02 phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1]octan-3-ol 159 J 4-[4-(3-Methoxy-4-phenoxy- 467.24.77 phenylamino)-quinazolin-6-ylethynyl]- piperidin-4-ol 160 J4-[4-(3-Chloro-4-phenoxy- 471.1 5.26phenylamino)-quinazolin-6-ylethynyl]- piperidin-4-ol 161 J4-[4-(3-Methyl-4-phenoxy- 451.2 5.09phenylamino)-quinazolin-6-ylethynyl]- piperidin-4-ol 162 I4-[4-(1-Benzenesulfonyl-1H-indol-5- 525.1 6.02 ylamino)-quinazolin-7-ylethynyl]-tetrahydro-pyran-4-ol 163 I 4-[4-(4-Phenoxy-phenylamino)-438.1 6.25 quinazolin-7-ylethynyl]-tetrahydro- pyran-4-ol 164 J1-(3-Aza-bicyclo[3.1.0]hex-6-yl(1α, 479.1 5.73 5α,6α))-3-[4-(3-methoxy-4-phenoxy- phenylamino)-quinazolin-6-yl]-prop-2-yn-1-ol 165 J 1-(3-Aza-bicyclo[3.1.0]hex-6-yl(1α, 463.1 5.16 5α,6α))-3-[4-(3-methyl-4-phenoxy- phenylamino)-quinazolin-6-yl]-prop-2-yn-1-ol 166 J 1-(3-Aza-bicyclo[3.1.0]hex-6-yl(1α, 449.0 4.89 5α,6α))-3-[4-(4-phenoxy- phenylamino)-quinazolin-6-yl]-prop-2- yn-1-ol 167J 3-[4-(4-Phenoxy-phenylamino)- 437.2 5.09quinazolin-7-ylethynyl]-piperidin-3-ol 168 J 3-[4-(3-Methoxy-4-phenoxy-467.2 4.97 phenylamino)-quinazolin-7-ylethynyl]- piperidin-3-ol 169 J3-[4-(3-Chloro-4-phenoxy- 471.1 5.48phenylamino)-quinazolin-7-ylethynyl]- piperidin-3-ol 170 J3-[4-(3-Methyl-4-phenoxy- 451.2 5.35phenylamino)-quinazolin-7-ylethynyl]- piperidin-3-ol 171 O4-Amino-1-[4-(3-methoxy-4-phenoxy- 455.2 4.91phenylamino)-quinazolin-6-yl]-4- methyl-pent-1-yn-3-ol 172 O4-Amino-4-methyl-1-[4-(3-methyl-4- 439.2 5.26phenoxy-phenylamino)-quinazolin-6- yl]-pent-1-yn-3-ol 173 J3-[4-(3-Ethynyl-phenylamino)- 369.2 4.11quinazolin-6-ylethynyl]-piperidin-3-ol 174 J3-[4-(3-Chloro-4-fluoro-phenylamino)- 397.1 4.43quinazolin-6-ylethynyl]-piperidin-3-ol 175 J[6-(4-Amino-tetrahydro-pyran-4- 451.2 5.43ylethynyl)-quinazolin-4-yl]-(3-methyl- 4-phenoxy-phenyl)-amine 176 J[6-(4-Amino-tetrahydro-pyran-4- 437.2 5.15ylethynyl)-quinazolin-4-yl]-(4- phenoxy-phenyl)-amine 177 J[6-(4-Amino-tetrahydro-pyran-4- 467.2 5.00ylethynyl)-quinazolin-4-yl]-(3- methoxy-4-phenoxy-phenyl)-amine 178 J(3-Methoxy-4-phenoxy-phenyl)-(6- 451.0 5.25piperidin-2-ylethynyl-quinazolin-4-yl)- amine 179 J(3-Methyl-4-phenoxy-phenyl)-(6- 435.0 5.71piperidin-2-ylethynyl-quinazolin-4- yl)-amine 180 J(4-Phenoxy-phenyl)-(6-piperidin-2- 421.2 5.32ylethynyl-quinazolin-4-yl)-amine 181 J (3-Chloro-4-phenoxy-phenyl)-(6-455.0 5.84 piperidin-2-ylethynyl-quinazolin-4-yl)- amine 182 J3-[4-(4-Phenoxy-phenylamino)- 451.2 5.16quinazolin-6-yl]-1-piperidin-2-yl-prop- 2-yn-1-ol 183 J3-[4-(3-Methyl-4-phenoxy- 465.2 5.44 phenylamino)-quinazolin-6-yl]-1-piperidin-2-yl-prop-2-yn-1-ol 184 J 3-[4-(3-Chloro-4-phenoxy- 485.1 5.58phenylamino)-quinazolin-6-yl]-1- piperidin-2-yl-prop-2-yn-1-ol 185 J3-[4-(3-Methoxy-4-phenoxy- 481.2 5.05 phenylamino)-quinazolin-6-yl]-1-piperidin-2-yl-prop-2-yn-1-ol 186 J (4-Phenoxy-phenyl)-(6-piperidin-3-421.2 5.27 ylethynyl-quinazolin-4-yl)-amine 187 J(3-Methoxy-4-phenoxy-phenyl)-(6- 451.2 5.21piperidin-3-ylethynyl-quinazolin-4-yl)-amine 188 J(3-Chloro-4-phenoxy-phenyl)-(6- 455.0 5.79piperidin-3-ylethynyl-quinazolin-4-yl)-amine 189 J3-[4-(4-Phenoxy-phenylamino)- 451.0 5.00quinazolin-6-yl]-1-piperidin-3-yl- prop-2-yn-1-ol 190 J3-[4-(3-Methyl-4-phenoxy- 465.0 5.26 phenylamino)-quinazolin-6-yl]-1-piperidin-3-yl-prop-2-yn-1-ol 191 J 3-[4-(3-Methoxy-4-phenoxy- 481.04.86 phenylamino)-quinazolin-6-yl]-1- piperidin-3-yl-prop-2-yn-1-ol 192J 3-[4-(3-Chloro-4-phenoxy- 485.0 5.34 phenylamino)-quinazolin-6-yl]-1-piperidin-3-yl-prop-2-yn-1-ol 193 I 1-Methyl-4-[4-(3-methyl-4-phenoxy-465.0 5.18 phenylamino)-quinazolin-6-ylethynyl]- piperidin-4-ol 194 I4-[4-(3-Chloro-4-phenoxy- 485.0 5.34phenylamino)-quinazolin-6-ylethynyl]- 1-methyl-piperidin-4-ol 195 I4-[4-(3-Methoxy-4-phenoxy- 481.0 4.81phenylamino)-quinazolin-6-ylethynyl]- 1-methyl-piperidin-4-ol 196 IN,N-Diethyl-3-[6-(4-hydroxy- 445.3 4.66 tetrahydro-pyran-4-ylethynyl)-quinazolin-4-ylamino]-benzamide 197 A(3-{3-[4-(1-Benzenesulfonyl-1H-indol- 550.3 5.385-ylamino)-quinazolin-6-yl]-prop-2- ynyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 198 I 4-{4-[1-(Propane-2-sulfonyl)-1H-indol- 491.2 5.665-ylamino]-quinazolin-6-ylethynyl}- tetrahydro-pyran-4-ol 199 I4-[4-(1H-Indol-5-ylamino)-quinazolin- 385.2 4.226-ylethynyl]-tetrahydro-pyran-4-ol 200 A 1-Methyl-3-[4-(4-phenoxy- 451.35.04 phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 201 J3-[4-(3-Chloro-4-phenoxy- 471.0 5.40 phenylamino)-quinazolin-6-yl]-1-pyrrolidin-2-yl-prop-2-yn-1-ol 202 I 1-[4-(1-Benzenesulfonyl-1H-indol-5-430.1 7.57 ylamino)-quinazolin-6-yl]-pent-1-yn-3-ol 203 I1-{4-[1-(Propane-2-sulfonyl)-1H-indol- 449.2 6.285-ylamino]-quinazolin-6-yl}-pent-1-yn-3-ol 204 I1-[4-(3-Chloro-4-phenoxy- 430.1 7.57phenylamino)-quinazolin-6-yl]-pent-1- yn-3-ol 205 I1-[4-(3-Methyl-4-phenoxy- 410.2 7.39phenylamino)-quinazolin-6-yl]-pent-1- yn-3-ol 206 I1-[4-(1-Benzyl-1H-indazol-5-ylamino) 434.2 6.16quinazolin-6-yl]-pent-1-yn-3-ol 207 I 1-[4-(4-Phenoxy-phenylamino)-396.2 7.04 quinazolin-6-yl]-pent-1-yn-3-ol 208 I3-{4-[4-(3-Fluoro-phenoxy)-3-methyl- 469.1 5.32phenylamino]-quinazolin-6-ylethynyl}- piperidin-3-ol 209 J3-{4-[4-(4-Methoxy-phenoxy)-3- 481.2 5.10methyl-phenylamino]-quinazolin-6- ylethynyl}-piperidin-3-ol 210 J4-Amino-1-[4-(3-methyl-4-phenoxy- 425.2 5.13phenylamino)-quinazolin-6-yl]-pent-1- yn-3-ol 211 J4-Amino-1-[4-(4-phenoxy- 410.3 4.86phenylamino)-quinazolin-6-yl]-pent-1- yn-3-ol 212 J4-Amino-1-[4-(3-chloro-4-phenoxy- 445.2 5.27phenylamino)-quinazolin-6-yl]-pent-1- yn-3-ol 213 J4-Amino-1-{4-[1-(propane-2-sulfonyl)- 464.1 4.371H-indol-5-ylamino]-quinazolin-6-yl}- pent-1-yn-3-ol 214 J4-Amino-1-{4-[4-(3-fluoro-phenoxy)-3- 443.2 5.25methyl-phenylamino]-quinazolin-6-yl}- pent-1-yn-3-ol 215 J3-{4-[4-(4-Fluoro-phenoxy)-3-methyl- 469.2 5.28phenylamino]-quinazolin-6-ylethynyl}- piperidin-3-ol 216 J3-{4-[4-(2-Fluoro-phenoxy)-3-methyl- 469.2 5.22phenylamino]-quinazolin-6-ylethynyl}- piperidin-3-ol 217 J3-[4-(3-Methoxy-4-phenoxy- 467.2 4.85phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 218 J3-{4-[1-(3-Fluoro-benzyl)-1H-indazol- 493.2 4.235-ylamino]-quinazolin-6-ylethynyl}- piperidin-3-ol 219 J3-{4-[1-(3-Methoxy-benzyl)-1H- 505.11 4.41indazol-5-ylamino]-quinazolin-6- ylethynyl}-piperidin-3-ol 220 J3-{4-[1-(3-Methyl-benzyl)-1H-indazol- 489.2 4.705-ylamino]-quinazolin-6-ylethynyl}- piperidin-3-ol 221 J3-{4-[1-(2-Fluoro-benzyl)-1H-indazol- 493.2 4.475-ylamino]-quinazolin-6-ylethynyl}- piperidin-3-ol 222 J2-Chloro-N,N-diethyl-4-[6-(3-hydroxy- 478.2 4.08piperidin-3-ylethynyl)-quinazolin-4- ylamino]-benzamide 223 J3-[4-(3-Bromo-4-phenoxy- 516.0 5.41phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 224 J3-[4-(3,5-Dichloro-4-phenoxy- 506.1 5.64phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 225 J3-[4-(3-Methyl-4-phenylsulfanyl- 467.2 5.64phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 226 J3-[4-(3-Methoxy-4-phenoxy- 453.2 4.76phenylamino)-quinazolin-6-ylethynyl]- pyrrolidin-3-ol 227 J4-Amino-1-[4-(3-methoxy-4-phenoxy- 441.2 4.78phenylamino)-quinazolin-6-yl]-pent-1- yn-3-ol 228 J1-[4-(3-Methoxy-4-phenoxy- 426.2 6.83phenylamino)-quinazolin-6-yl]-pent-1- yn-3-ol 229 J3-[4-(4-Benzenesulfinyl-3-methyl- 483.1 4.08phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 230 J3-[4-(4-Benzenesulfonyl- 485.1 4.49phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 231 J3-[4-(4-Benzenesulfinyl- 469.1 3.89phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 232 J3-[4-(4-Benzenesulfonyl-3-methyl- 499.1 4.65phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 233 J3-[4-(4-Cyclopentyloxy-3-methyl- 443.2 5.30phenylamino)-quinazolin-6-ylethynyl]- Piperidin-3-ol 234 J3-[4-(4-Cyclobutoxy-3-methyl- 429.2 4.97phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 235 J5-[6-(3-Hydroxy-piperidin-3-ylethynyl)- 462.2 4.86quinazolin-4-ylamino]-2-phenoxy- benzonitrile 236 J3-[4-(4-Cyclohexyloxy-3-methyl- 457.3 5.62phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 237 J3-[4-(4-Phenylamino-phenylamino)- 436.2 4.58quinazolin-6-ylethynyl]-piperidin-3-ol 238 J3-[4-(3-Phenyl-1H-indazol-6-ylamino)- 461.2 3.86quinazolin-6-ylethynyl]-piperidin-3-ol 239 I 4-[4-(3-Methyl-4-phenoxy-410.2 7.22 phenylamino)-quinazolin-6-yl]-2- methyl-but-3-yn-2-ol 240 I4-[4-(3-Chloro-4-phenoxy- 430.1 7.39 phenylamino)-quinazolin-6-yl]-2-methyl-but-3-yn-2-ol 241 I 4-[4-(3-Methoxy-4-phenoxy- 426.2 6.67phenylamino)-quinazolin-6-yl]-2- methyl-but-3-yn-2-ol 242 I[6-(3-Methyl-but-1-ynyl)-quinazolin-4- 394.2 9.08yl]-(3-methyl-4-phenoxy-phenyl)-amine 243 I(3-Methoxy-4-phenoxy-phenyl)-[6-(3- 410.2 8.47methyl-but-1-ynyl)-quinazolin-4-yl]-amine 244 I(3-Chloro-4-phenoxy-phenyl)-[6-(3- 414.1 9.21methyl-but-1-ynyl)-quinazolin-4-yl]-amine 245 J 3-[4-(4-Benzyl-3-methyl-449.2 5.37 phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 246 J[6-(3-Amino-3-methyl-but-1-ynyl)- 395.2 5.13quinazolin-4-yl]-(3-methyl-4-phenoxy- phenyl)-amine 247 J[6-(3-Amino-3-methyl-but-1-ynyl)- 409.2 5.45quinazolin-4-yl]-(4-phenoxy-phenyl)- amine 248 J[6-(3-Amino-3-methyl-but-1-ynyl)- 425.2 5.04quinazolin-4-yl]-(3-methoxy-4- phenoxy-phenyl)-amine 249 J[6-(3-Amino-3-methyl-but-1-ynyl)- 429.1 5.56quinazolin-4-yl]-(3-chloro-4-phenoxy- phenyl)-amine 250 J[6-(3-Amino-prop-1-ynyl)-quinazolin- 367.2 4.784-yl]-(4-phenoxy-phenyl)-amine 251 J[6-(3-Amino-prop-1-ynyl)-quinazolin- 381.2 5.094-yl]-(3-methyl-4-phenoxy-phenyl)-amine 252 J[6-(3-Amino-prop-1-ynyl)-quinazolin- 397.2 4.724-yl]-(3-methoxy-4-phenoxy-phenyl)-amine 253 J[6-(3-Amino-prop-1-ynyl)-quinazolin- 401.1 5.284-yl]-(3-chloro-4-phenoxy-phenyl)-amine 254 J[6-(3-Methylamino-prop-1-ynyl)- 381.2 5.05quinazolin-4-yl]-(4-phenoxy-phenyl)-amine 255 J[6-(3-Methylamino-prop-1-ynyl)- 395.2 5.32quinazolin-4-yl]-(3-methyl-4-phenoxy- phenyl)-amine 256 J(3-Methoxy-4-phenoxy-phenyl)-[6-(3- 411.2 4.87methylamino-prop-1-ynyl)-quinazolin- 4-yl]-amine 257 J(3-Chloro-4-phenoxy-phenyl)-[6-(3- 415.1 5.45methylamino-prop-1-ynyl)-quinazolin- 4-yl]-amine 258 A[6-(3-Dimethylamino-prop-1-ynyl)- 409.3 5.94quinazolin-4-yl]-(3-methyl-4-phenoxy phenyl)-amine 259 J3-[4-(3-Ethyl-4-phenoxy- 465.2 5.54phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 260 J3-[4-(3-Methyl-4-p-tolyloxy- 465.2 5.52phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 261 J3-[4-(3-Hydroxy-4-phenoxy- 453.1 4.34phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 262 J2-Amino-4-[4-(3-methyl-4-phenoxy- 411.2 4.95phenylamino)-quinazolin-6-yl]-but-3- yn-1-ol 263 J2-Amino-4-[4-(3-methoxy-4-phenoxy- 427.1 4.60phenylamino)-quinazolin-6-yl]-but-3- yn-1-ol 264 J3-[4-(3-Ethoxy-4-phenoxy- 481.1 5.59phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 265 J3-[4-(3-Isopropoxy-4-phenoxy- 495.2 5.40phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 266 J3-[4-(2-Fluoro-4-phenoxy- 455.2 4.9phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 267 J3-[4-(4-Fluoro-2-phenoxy- 455.2 4.61phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 268 J3-[4-(4-Pyridin-2-ylmethyl- 436.2 3.59phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol 269 J2-Amino-1-[4-(3-methyl-4-phenoxy- 465.1 5.45phenylamino)-quinazolin-6-ylethynyl]- cyclohexanol 270 J2-Amino-1-[4-(3-methoxy-4-phenoxy- 481.2 5.10phenylamino)-quinazolin-6-ylethynyl]- cyclohexanol 271 J1-Methylamino-4-[4-(3-methyl-4- 425.2 5.08phenoxy-phenylamino)-quinazolin-6- yl]-but-3-yn-2-ol 272 J4-[4-(3-Methoxy-4-phenoxy- 441.2 4.76 phenylamino)-quinazolin-6-yl]-1-methylamino-but-3-yn-2-ol 273 A′ (3-Methyl-4-phenoxy-phenyl)-[6-(3-450.0 5.25 piperazin-1-yl-prop-1-ynyl)-quinazolin- 4-yl]-amine 274 A(3-Methyl-4-phenoxy-phenyl)-[6-(3- 435.0 5.95pyrrolidin-1-yl-prop-1-ynyl)-quinazolin- 4-yl]-amine 275 A′(3-Methoxy-4-phenoxy-phenyl)-[6-(3- 466.3 4.95piperazin-1-yl-prop-1-ynyl)- quinazolin-4-ayl]-amine 276 I3-[4-(3-Methyl-4-phenoxy- 477.2 5.31phenylamino)-quinazolin-6-ylethynyl]- 1-aza-bicyclo[2.2.2]octan-3-ol 277J 3-{4-[4-(2,6-Difluoro-phenoxy)-3- 487.0 5.22methyl-phenylamino]-quinazolin-6- ylethynyl}-piperidin-3-ol 278 A′{6-[3-(6-Amino-3-aza- 462.3 5.38 bicyclo[3.1.0]hex-3-yl(1α, 5α, 6α))-prop-1-ynyl]-quinazolin-4-yl}-(3- methyl-4-phenoxy-phenyl)-amine 279 A(3-Methyl-4-phenoxy-phenyl)-[6-(3- 451.0 7.27morpholin-4-yl-prop-1-ynyl)- quinazolin-4-yl]-amine 280 A(3-{3-[4-(3-Methyl-4-phenoxy- 477.3 5.70phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-3-aza-bicyclo[3.1.0]hex-6-yl(1α, 5α, 6α))-methanol 281 A′(3-Methyl-4-phenoxy-phenyl)-{6-[3- 464.1 5.49(2-methyl-piperazin-1-yl)-prop-1-ynyl]- quinazolin-4-yl}-amine 282 A′{6-[3-(2,6-Dimethyl-piperazin-1-yl)- 478.3 5.57prop-1-ynyl]-quinazolin-4-yl}-(3- methyl-4-phenoxy-phenyl)-amine 283 A(3-Methyl-4-phenoxy-phenyl)-{6-[3- 464.0 5.60(4-methyl-piperazin-1-yl)-prop-1-ynyl]- quinazolin-4-yl}-amine 284 A1-{3-[4-(3-Methyl-4-phenoxy- 465.0 5.45phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperidin-4-ol 285 A1-{3-[4-(3-Methyl-4-phenoxy- 451.3 5.38phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-pyrrolidin-3-ol 286 K(3-Methyl-4-phenoxy-phenyl)-[6-(1- 449.5 5.86methyl-piperidin-3-ylethynyl)- quinazolin-4-yl]-amine 287 A(1-{3-[4-(3-Methyl-4-phenoxy- 465.3 5.51phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-pyrrolidin-2-yl)-methanol288 A (1-{3-[4-(3-Methyl-4-phenoxy- 479.1 5.58phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperidin-2-yl)-methanol 289A (1-{3-[4-(3-Methyl-4-phenoxy- 478.9 5.59phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperidin-3-yl)-methanol 290A 2-(Methyl-{3-[4-(3-methyl-4-phenoxy- 439.1 5.45phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-amino)-ethanol 291 A′3-Methyl-2-{3-[4-(3-methyl-4- 467.4 5.72phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynylamino}-butan-1-ol 292A (3-Methyl-4-phenoxy-phenyl)-[6-(2- 439.3 5.33piperidin-3-yl-ethyl)-quinazolin-4-yl]- amine 293 A4-[4-(3-Methyl-4-phenoxy- 452.1 6.76phenylamino)-quinazolin-6-ylethynyl]- tetrahydro-pyran-4-ol 294 A4-[4-(3-Chloro-4-phenoxy- 471.9 6.94phenylamino)-quinazolin-6-ylethynyl]- tetrahydro-pyran-4-ol 295 K4-[4-(3-Methoxy-4-phenoxy- 467.9 6.23phenylamino)-quinazolin-6-ylethynyl]- tetrahydro-pyran-4-ol 296 A4-Methyl-2-{3-[4-(3-methyl-4- 481.0 5.99phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynylamino}-pentan-1-ol 297A′ 3-{3-[4-(3-Methyl-4-phenoxy- 495.0 4.94phenylamino)-quinazolin-6-yl]-prop-2- ynylamino}-propane-1,2-diol 298 A1-{3-[4-(3-Methyl-4-phenoxy- 493.3 7.90phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-pyrrolidine-2-carboxylicacid methyl ester 299 K (3-Methyl-4-phenoxy-phenyl)-[6-(1- 477.1 6.24propyl-piperidin-3-ylethynyl)- quinazolin-4-yl]-amine 300 A′{6-[3-(4-Amino-piperidin-1-yl)-prop-1- 464.3 5.10ynyl]-quinazolin-4-yl}-(3-methyl-4- phenoxy-phenyl)-amine 301 K′{6-[1-(2-Amino-ethyl)-piperidin-3- 478.1 5.84ylethynyl]-quinazolin-4-yl}-(3-methyl- 4-phenoxy-phenyl)-amine 302 A1-{3-(4-(3-Methoxy-4-phenoxy- 509.0 7.37phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-pyrrolidine-2-carboxylicacid methyl ester 303 A (1-{3-[4-(3-Methyl-4-phenoxy- 479.3 5.40phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperidin-4-yl)-methanol 304A (1-{3-[4-(3-Methoxy-4-phenoxy- 495.3 4.99phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperidin-4-yl)-methanol 305A {6-[3-(4,4-Dimethoxy-piperidin-1-yl)- 509.2 7.33prop-1-ynyl]-quinazolin-4-yl}-(3- methyl-4-phenoxy-phenyl)-amine 306 A{6-[3-(3-Dimethylamino-pyrrolidin-1- 478.3 5.85yl)-prop-1-ynyl]-quinazolin-4yl}-(3- methyl-4-phenoxy-phenyl)-amine 307A 2-(1-{3-[4-(3-Methyl-4-phenoxy- 493.1 5.50phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperidin-4-yl)-ethanol 308K′ {6-[1-(2-Amino-propyl)-piperidin-3- 492.4 6.28ylethynyl]-quinazolin-4-yl}-(3-methyl- 4-phenoxy-phenyl)-amine 309 K2-{3-[4-(3-Methyl-4-phenoxy- 479.3 5.66phenylamino)-quinazolin-6-ylethynyl]- piperidin-1-yl}-ethanol 310 J3-[4-(4-Bromo-2-fluoro-phenylamino)- 442.9, 4.26quinazolin-6-ylethynyl]-piperidin-3-ol 440.9 311 J3-[4-(4-Bromo-2,6-difluoro- 460.9, 4.24phenylamino)-quinazolin-6-ylethynyl]- 459.1 piperidin-3-ol 312 K{6-[1-(2-Methoxy-ethyl)-piperidin-3- 493.1 6.05ylethynyl]-quinazolin-4-yl}-(3-methyl- 4-phenoxy-phenyl)-amine 314 J6-Hydroxymethyl-3-[4-(3-methyl-4- 424.2 8.64phenoxy-phenylamino)-quinazolin-6- ylethynyl]-piperidin-3-ol 315 A′{6-[3-(2,5-Diaza-bicyclo[2.2.1]hept-2- 478.2 4.92yl)-prop-1-ynyl]-quinazolin-4-yl}-(3- methoxy-4-phenoxy-phenyl)-amine316 A {6-[3-(6-Dimethylamino-3-aza- 506.1 5.28bicyclo[3.1.0]hex-3-yl(1α, 5α, 6α))- prop-1-ynyl]-quinazolin-4-yl}-(3-methoxy-4-phenoxy-phenyl)-amine 317 J5-Hydroxy-5-[4-(3-methyl-4-phenoxy- 494.0 5.11phenylamino)-quinazolin-6-ylethynyl]- piperidine-2-carboxylic acid amide318 A 2-(4-{3-[4-(3-Methyl-4-phenoxy- 494.4 5.17phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperazin-1-yl)-ethanol 319A 2-(4-{3-[4-(3-Methoxy-4-phenoxy- 510.1 4.89phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperazin-1-yl)-ethanol 320J 3-Hydroxymethyl-4-[4-(3-methyl-4- 481.0 4.94phenoxy-phenylamino)-quinazolin-6- ylethynyl]-piperidin-4-ol 321 J3-Hydroxymethyl-4-[4-(3-methoxy-4- 497.0 4.63phenoxy-phenylamino)-quinazolin-6- ylethynyl]-piperidin-4-ol 322 A1-{3-[4-(3-Methyl-4-phenoxy- 463.1 7.17phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperidin-4-one 323 J(3-Methyl-4-phenoxy-phenyl)-[6-(3- 467.3 8.06thiomorpholin-4-yl-prop-1-ynyl)- quinazolin-4-yl]-amine 324 J5-Hydroxymethyl-3-[4-(3-methyl-4- 466.9 5.04phenoxy-phenylamino)-quinazolin-6- ylethynyl]-pyrrolidin-3-ol 325 J5-Hydroxymethyl-3-[4-(3-methoxy-4- 482.9 4.72phenoxy-phenylamino)-quinazolin-6- ylethynyl]-pyrrolidin-3-ol 326 A1-{3-[4-(3-Methyl-4-phenoxy- 478.3 6.43phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperidin-4-one oxime 327 J2-Hydroxymethyl-3-[4-(3-methyl-4- 482.0 6.13phenoxy-phenylamino)-quinazolin-6- ylethynyl]-tetrahydro-pyran-3-ol 328A 4-{3-[4-(3-Methyl-4-phenoxy- 522.1 7.78phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperazine-1-carboxylic acidethyl ester 329 A 4-{3-[4-(3-Methoxy-4-phenoxy- 538.3 7.16phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperazine-1-carboxylic acidethyl ester 330 J 4-Hydroxy-4-[4-(3-methoxy-4- 496.1 4.70phenoxy-phenylamino)-quinazolin-6- ylethynyl]-pyrrolidine-2-carboxylicacid amide 331 J 4-[4-(3-Chloro-4-phenoxy- 500.2 5.21phenylamino)-quinazolin-6-ylethynyl]- 4-hydroxy-pyrrolidine-2-carboxylicacid amide 332 J 4-Hydroxy-4-[4-(3-methyl-4-phenoxy- 480.3 5.03phenylamino)-quinazolin-6-ylethynyl]- pyrrolidine-2-carboxylic acidamide 333 A N-{3-[4-(3-Methyl-4-phenoxy- 459.0 6.85phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-methanesulfonamide 334 A1-(4-{3-[4-(3-Methyl-4-phenoxy- 492.3 6.39phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperazin-1-yl)-ethanone 335I 4-Hydroxy-4-[4-(3-methyl-4-phenoxy- 495.3 5.90phenylamino)-quinazolin-6-ylethynyl]- tetrahydro-pyran-2-carboxylic acidamide 336 J 4-Hydroxy-4-[4-(3-methoxy-4- 511.1 5.49phenoxy-phenylamino)-quinazolin-6- ylethynyl]-tetrahydro-pyran-2-carboxylic acid amide 337 J 4-[4-(3-Chloro-4-phenoxy- 515.2 6.09phenylamino)-quinazolin-6-ylethynyl]- 4-hydroxy-tetrahydro-pyran-2-carboxylic acid amide 338 A N-{3-[4-(3-Methoxy-4-phenoxy- 475.1 6.40phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-methanesulfonamide 339 A{6-[3-(4-Methanesulfonyl-piperazin-1- 528.1 7.08yl)-prop-1-ynyl]-quinazolin-4-yl}-(3- methyl-4-phenoxy-phenyl)-amine 340A 4-{3-[4-(3-Methyl-4-phenoxy- 507.3 6.12phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperazine-1-carboxylic acidmethylamide 341 A 4-{3-[4-(3-Methoxy-4-phenoxy- 523.2 5.64phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperazine-1-carboxylic acidmethylamide 342 A {6-[3-(4-Methanesulfonyl-piperazin-1- 544.1 6.54yl)-prop-1-ynyl]-quinazolin-4-yl}-(3- methoxy-4-phenoxy-phenyl)-amine343 J 2-Hydroxymethyl-4-[4-(3-methyl-4- 482.3 5.85phenoxy-phenylamino)-quinazolin-6- ylethynyl]-tetrahydro-pyran-4-ol 344J 2-Hydroxymethyl-4-[4-(3-methoxy-4- 498.3 5.43phenoxy-phenylamino)-quinazolin-6- ylethynyl]-tetrahydro-pyran-4-ol 345J 4-[4-(3-Chloro-4-phenoxy- 502.2 6.04phenylamino)-quinazolin-6-ylethynyl]-2-hydroxymethyl-tetrahydro-pyran-4-ol 346 A{6-[3-(1,1-Dioxo-1&-isothiazolidin-2- 485.3 7.30yl)-prop-1-ynyl]-quinazolin-4-yl}-(3- methyl-4-phenoxy-phenyl)-amine 347A {6-[3-(1,1-Dioxo-1&-isothiazolidin-2- 501.3 6.69yl)-prop-1-ynyl]-quinazolin-4-yl}-(3- methoxy-4-phenoxy-phenyl)-amine348 I N-{3-[4-(4-Phenoxy-phenylamino)- 409.0 6.03quinazolin-6-yl]-prop-2-ynyl}- acetamide 349 IN-{3-[4-(3-Chloro-4-phenoxy- 442.9 6.55phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-acetamide 350 A{6-[3-(1,1-Dioxo-1&-thiomorpholin-4- 515.2 6.40yl)-prop-1-ynyl]-quinazolin-4-yl}-(3- methoxy-4-phenoxy-phenyl)-amine351 A 4-{3-[4-(3-Methyl-4-phenoxy- 536.6 6.04phenylamino)-quinazolin-6-yl]-prop-2- ynylamino}-piperidine-1-carboxylicacid ethyl ester 352 A 4-{3-[4-(3-Methoxy-4-phenoxy- 552.3 5.97phenylamino)-quinazolin-6-yl]-prop-2- ynylamino}-piperidine-1-carboxylicacid ethyl ester 353 J N-{3-[4-(3-Methyl-4-phenoxy- 451.3 7.09phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-isobutyramide 354 J[4-(2-Fluoro-phenoxy)-3-methyl- 453.4 5.55phenyl]-(6-piperidin-3-ylethynyl- quinazolin-4-yl)-amine 355 J[4-(3-Fluoro-phenoxy)-3-methyl- 453.4 5.75phenyl]-(6-piperidin-3-ylethynyl- quinazolin-4-yl)-amine 356 IN-Methyl-N-{3-[4-(4-phenoxy- 423.3 6.53phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-acetamide 357 IN-Methyl-N-{3-[4-(3-methyl-4- 437.3 6.86phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynyl}-acetamide 358 IN-{3-[4-(3-Chloro-4-phenoxy- 457.3 7.05phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-N-methyl-acetamide 359 I2,2-Dimethyl-N-{3-[4-(3-methyl-4- 465.0 7.57phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynyl}-propionamide 360 J(3-Methyl-4-phenoxy-phenyl)-(6- 421.3 5.43pyrrolidin-3-ylethynyl-quinazolin-4-yl)- amine 361 J[4-(2-Fluoro-phenoxy)-3-methyl- 439.0 5.39phenyl]-(6-pyrrolidin-3-ylethynyl- quinazolin-4-yl)-amine 362 J(3-Chloro-4-phenoxy-phenyl)-(6- 441.0 5.61pyrrolidin-3-ylethynyl-quinazolin-4-yl)- amine 363 J(3-Methoxy-4-phenoxy-phenyl)-(6- 437.1 5.06pyrrolidin-3-ylethynyl-quinazolin-4-yl)- amine 364 I2-Chloro-N-{3-[4-(3-methyl-4- 457.0 7.00phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynyl}-acetamide 365 ICyclopropanecarboxylic acid {3-[4-(3- 449.1 6.97methyl-4-phenoxy-phenylamino)- quinazolin-6-yl]-prop-2-ynyl}-amide 366 IN-{3-[4-(3-Methyl-4-phenoxy- 437.1 6.74phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-propionamide 367 I2-Methoxy-N-{3-[4-(3-methyl-4- 453.2 6.69phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynyl}-acetamide 368 MN-{3-[4-(3-Methyl-4-phenoxy- 508.0 6.49phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-2-morpholin-4-yl-acetamide369 A′ 1-{3-[4-(3-Methyl-4-phenoxy- 508.0 5.66phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperazine-2-carboxylic acidmethyl ester 370 A 4-{3-[4-(3-Methyl-4-phenoxy- 493.5 5.87phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-piperazine-1-carboxylic acidamide 371 J (−)-(3-Methyl-4-phenoxy-phenyl)-(6- 435.1 5.61piperidin-3(S)-ylethynyl-quinazolin-4- yl)-amine 372 A′4-Aminomethyl-1-{3-[4-(3-methyl-4- 480.3 4.95phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynyl}-pyrrolidin-3-ol 373J 4-Hydroxy-4-[4-(3-methyl-4-phenoxy- 494.0 5.18phenylamino)-quinazolin-6-ylethynyl]- pyrrolidine-2-carboxylic acidmethylamide 374 N (3-Methyl-4-phenoxy-phenyl)-(6- 436.3 5.40piperidin-3-ylethynyl-pyrido[3,4- d]pyrimidin-4-yl)-amine 375 N(3-Methyl-4-phenoxy-phenyl)-(6- 436.3 5.32piperidin-4-ylethynyl-pyrido[3,4- d]pyrimidin-4-yl)-amine 376 J(3-Methoxy-4-phenoxy-phenyl)-(6- 451.3 5.17piperidin-4-ylethynyl-quinazolin-4-yl)- amine 377 J(3-Chloro-4-phenoxy-phenyl)-(6- 455.0 5.73piperidin-4-ylethynyl-quinazolin-4-yl)- amine 378 J(3-Methyl-4-phenoxy-phenyl)-(6- 435.1 5.56piperidin-4-ylethynyl-quinazolin-4-yl)- amine 379 A3(S)-[4-(3-Methyl-4-phenoxy- 492.3 7.15phenylamino)-quinazolin-6-ylethynyl]- piperidine-1-carboxylic acidmethylamide 380 I 3(S)-[4-(3-Methoxy-4-phenoxy- 509.4 6.65phenylamino)-quinazolin-6-ylethynyl]- piperidine-1-carboxylic acidmethylamide 381 I N-{1,1-Dimethyl-3-[4-(3-methyl-4- 505.0 8.15phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynyl}-2,2,2-trifluoro-acetamide 382 J (+)-(3-Methyl-4-phenoxy-phenyl)-(6- 435.3 5.61piperidin-3(R)-ylethynyl-quinazolin-4- yl)-amine 383 IN-{1,1-Dimethyl-3-[4-(3-methyl-4- 451.2 7.00phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynyl}-acetamide 384 IN-{3-[4-(3-Chloro-4-phenoxy- 471.1 7.22phenylamino)-quinazolin-6-yl]-1,1- dimethyl-prop-2-ynyl}-acetamide 385 J[4-(2-Chloro-phenoxy)-3-methyl- 469.0 5.97phenyl]-(6-piperidin-3-ylethynyl- quinazolin-4-yl)-amine 386 J[4-(2-Methoxy-phenoxy)-3-methyl- 465.1 5.31phenyl]-(6-piperidin-3-ylethynyl- quinazolin-4-yl)-amine 387 J[3-Methyl-4-(2-trifluoromethyl- 503.0 6.17phenoxy)-phenyl]-(6-piperidin-3- ylethynyl-quinazolin-4-yl)-amine 388 J[4-(2-Ethyl-phenoxy)-3-methyl- 463.0 6.38phenyl]-(6-piperidin-3-ylethynyl- quinazolin-4-yl)-amine 389 J(6-Azetidin-3-ylethynyl-quinazolin-4- 407.3 5.31yl)-(3-methyl-4-phenoxy-phenyl)- amine 390 IN-{1-Methyl-3-[4-(3-chloro-4-phenoxy- 456.9 6.84phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-acetamide 391 IN-{1-Methyl-3-[4-(3-methyl-4- 437.1 6.65phenoxy-phenylamino)-quinazolin-6- yl]-prop-2-ynyl}-acetamide 392 IN-{3-[4-(3-Methyl-4-phenoxy- 422.8 6.36phenylamino)-quinazolin-6-yl]-prop-2- ynyl}-acetamide

[0353] Utilizing method I and the appropriate starting materials(prepared according to dology known in the art), the following compounds(and pharmaceutically acceptable and solvates thereof), which are partof the present invention, may be prepared:

[0354]1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-azetidin-1-yl}-ethanone

[0355]1-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-azetidin-1-yl}-ethanone

[0356]1-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yethynyl]-azetidin-1-yl}-ethanone

[0357][6-(1-Methanesulfonyl-azetidin-3-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0358][6-(1-Methanesulfonyl-azetidin-3-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine

[0359][6-(1-Methanesulfonyl-azetidin-3-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine

[0360][6-(1-Methanesulfonyl-pyrrolidin-3-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0361][6-(1-Methanesulfonyl-pyrrolidin-3-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine

[0362][6-(1-Methanesulfonyl-pyrrolidin-3-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine

[0363]1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-1-yl}-ethanone

[0364]1-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-1-yl-ethanone

[0365]1-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-1-yl}-ethanone

[0366]1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-1-yl}-ethanone

[0367]1-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-1-yl}-ethanone

[0368]1-3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-1-yl}-ethanone

[0369][6-(1-Methanesulfony-piperidin-3-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0370][6-(1-Methanesulfonyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine

[0371][6-(1-Methanesulfonyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine

[0372]5-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-2-one

[0373]5-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl-piperidin-2-one

[0374]5-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-2-one

[0375]4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-2-one

[0376]4-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-2-one

[0377]4-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-2-one

[0378]1-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-4-yl]-ethanone

[0379]1-2-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-4-yl}-ethanone

[0380]1-{2-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-4-yl}-ethanone

[0381][6-(4-Methanesulfonyl-morpholin-2-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0382][6-(4-Methanesulfonyl-morpholin-2-ylethynyl)-quinazolin-4-yl]-(3-methoxy4-phenoxy-phenyl)-amine

[0383][6-(4-Methanesulfonyl-morpholin-2-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine

[0384]6-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-3-one

[0385]6-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-3-one

[0386]6-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-3-one

[0387]5-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one

[0388]5-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one

[0389]5-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one

[0390]6-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one

[0391]6-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one

[0392]6-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one

[0393]1-{5-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,4-dihydro-2H-pyridin-1-yl}-ethanone

[0394]1-{5-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,4-dihydro-2H-pyridin-1-yl}-ethanone

[0395]1-{5-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,4-dihydro-2H-pyridin-1-yl}-ethanone

[0396][6-(1-Methanesulfonyl-1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0397][6-(1-Methanesulfonyl-1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine

[0398][6-(1-Methanesulfonyl-1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine

[0399]1-{5-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone

[0400]1-{5-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone

[0401]1-{5-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone

[0402][6-(1-Methanesulfonyl-1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0403][6-(1-Methanesulfonyl-1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine

[0404][6-(1-Methanesulfonyl-1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine

[0405]1-{4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone

[0406]1-{4-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone

[0407]1-{4-[4-(3-Choro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone

[0408][6-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0409][6-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine

[0410][6-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine

[0411]N-{1,1-Dimethyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide

[0412]N-{1,1-Dimethyl-3-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide

[0413]N-{1,1-Dimethyl-3-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide

[0414]N-{1,1-Dimethyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl-prop-2-ynyl}-methanesulfonamide

[0415]N-{1,1-Dimethyl-3-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-methanesulfonamide

[0416]N-{1,1-Dimethyl-3-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-methanesulfonamide

[0417]N-{1-Methyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazoin-6-yl]-prop-2-ynyl}-acetamide

[0418]N-{1-Methyl-3-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide

[0419]N-{1-Methyl-3-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide

[0420]N-{1-Methyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazoin-6-yl]-prop-2-ynyl}-methanesulfonamide

[0421]N-{1-Methyl-3-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-methanesulfonamide

[0422]N-{1-Methyl-3-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-methanesulfonamide

[0423]1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-2-one

[0424]1-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-2-one

[0425]1-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-2-one

[0426]1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-pyrrolidin-2-one

[0427]1-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-pyrrolidin-2-one

[0428]1-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-pyrrolidin-2-one

[0429] Utilizing method J and the appropriate starting materials(prepared according to methodology known in the art), the followingcompounds (and pharmaceutically acceptable salts and solvates thereof),which are part of the present invention, may be prepared:

[0430] (7-Methoxy-6-piperidin-3-ylethynyl-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine

[0431](3-Chloro-4-phenoxy-phenyl)-(7-methoxy-6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine

[0432](3-Methoxy-4-phenoxy-phenyl)-(7-methoxy-6-piperidin-3-ylethyny-quinazolin-4-yl)-amine

[0433](7-(2-Methoxy-ethoxy)-6-piperidin-3-ylethynyl-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0434](3-Chloro-4-phenoxy-phenyl)-[7-(2-methoxy-ethoxy)-6-piperidin-3-ylethynyl-quinazolin-4-yl]-amine

[0435][7-(2-Methoxy-ethoxy)-6-piperidin-3-ylethynyl-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine

[0436]3-[7-(2-Methoxy-ethoxy)-4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol

[0437]3-[7-(2-Methoxy-ethoxy)-4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol

[0438]3-[7-(2-Methoxy-ethoxy)-4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol

[0439]3-[7-Methoxy-4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol

[0440]3-[7-Methoxy-4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol

[0441]3-[7-Methoxy4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol

[0442] (6-Azetidin-3-ylethynyl-quinazolin-4-yl)-(3-methoxy4-phenoxy-phenyl)-amine

[0443](3-Methyl-4-phenoxy-phenyl)-(6-morpholin-2-ylethynyl-quinazolin-4-yl)-amine

[0444](3-Methoxy-4-phenoxy-phenyl)-(6-morpholin-2-ylethynyl-quinazolin-4-yl)-amine

[0445](3-Chloro-4-phenoxy-phenyl)-(6-morpholin-2-ylethynyl-quinazolin-4-yl)-amine

[0446](3-Methyl-4-phenoxy-phenyl)-[6-(1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-amine

[0447](3-Methoxy-4-phenoxy-phenyl)-[6-(1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-amine

[0448] (3-Chloro-4-phenoxy-phenyl)-[6-(1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-amine

[0449](3-Methyl-4-phenoxy-phenyl)-[6-(1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-amine

[0450](3-Methoxy-4-phenoxy-phenyl)-[6-(1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-amine

[0451](3-Chloro-4-phenoxy-phenyl)-[6-(1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-amine

[0452](3-Methyl-4-phenoxy-phenyl)-[6-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-amine

[0453](3-Methoxy-4-phenoxy-phenyl)-[6-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-amine

[0454](3-Chloro-4-phenoxy-phenyl)-[6-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-amine

[0455][6-(3-Amino-3-methyl-but-1-ynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0456][6-(3-Amino-3-methyl-but-1-ynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine

[0457][6-(3-Amino-3-methyl-but-1-ynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine

[0458][6-(3-Amino-but-1-ynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0459][6-(3-Amino-but-1-ynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

[0460][6-(3-Amino-but-1-ynyl)-quinazolin-4-y]-(3-methyl-4-phenoxy-phenyl)-amine

1. A compound of the formula I

or a pharmaceutically acceptable salt or solvate thereof, wherein: X isN or CH; A represents a fused 5, 6 or 7-membered ring optionallycontaining 1 to 4 heteroatoms which may be the same or different andwhich are selected from —N(R¹)—, O, and S(O)_(j), wherein j is aninteger from 0 to 2, the fused ring containing a total of 1, 2 or 3double bonds inclusive of the bond in the pyridine or pyrimidine ring towhich it is fused wherein the R¹ group attached to the nitrogen isabsent if a double bond includes the foregoing optional nitrogen moiety—N(R¹)—, with the proviso that the fused ring does not form part of apurine and that the fused ring does not contain two adjacent O orS(O)_(j) atoms, and wherein the carbon atoms of the A moiety areoptionally substituted with 1 to 3 R⁵ groups; each R¹ and R² isindependently H or C₁-C₆ alkyl; R³ is —(CR¹R²)_(m)—R⁸ wherein m is 0 or1; or R¹ and R³ are taken together to form a group of the formula

wherein said group is optionally substituted with 1 to 3 R⁵ groups; R⁴is —(CR¹R²)_(m)—C≡C—(CR¹R²)_(t)R⁹, —(CR¹R²)_(m)—C═C—(CR¹R²)_(t)—R⁹,—C═NOR¹², or —X¹—R¹² wherein m is an integer from 0 to 3, t is aninteger from 0 to 5, and X¹ is a divalent group derived from azetidine,oxetane or a C₃-C₄ carbocyclic group; or R⁴ is—(CR¹R²)_(m)—C≡C—(CR¹R²)_(k)R¹³ or —(CR¹R²)_(m)_C═C—(CR¹R²)_(k)R¹³wherein k is an integer from 1 to 3 and m is an integer from 0 to 3; orR⁴ is —(CR¹R²)_(t)R⁹, wherein t is an integer from 0 to 5 and theattachment point to R⁹ is through a carbon atom of the R⁹ group; each R⁵is independently selected from halo, hydroxy, —NR¹R², C₁-C₆ alkyl,trifluoromethyl, C₁-C₆ alkoxy, trifluoromethoxy, —C(O)R⁶, —CO₂R⁶,—NR⁶C(O)R¹, —C(O)NR⁶R⁷, —SO₂NR⁶R⁷, —NR⁶C(O)NR⁷R¹, and —NR⁶C(O)OR⁷; eachR⁶ and R⁷ is independently selected from H, C₁-C₆ alkyl,—(CR¹R²)_(t)(C₆-C₁₀ aryl), and —(CR¹R²)_(t)(4-10 membered heterocyclic),wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of theheterocyclic group are optionally substituted with an oxo (═O) moiety,and the alkyl, aryl and heterocyclic moieties of the foregoing R⁶ and R⁷groups are optionally substituted with 1 to 3 substituents independentlyselected from halo, cyano, nitro, —NR¹R², trifluoromethyl,trifluoromethoxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxy,and C₁-C₆ alkoxy; R⁸ is independently selected from —(CR¹R²)_(t)(C₆-C₁₀aryl) and —(CR¹R²)_(t)(4-10 membered heterocyclic), wherein t is aninteger from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic groupare optionally substituted with an oxo (═O) moiety, and each of theforegoing R⁸ groups is optionally substituted with 1 to 5 R¹⁰ groups; R⁹is a non-aromatic mono-cyclic ring, a fused or bridged bicyclic ring, ora spirocyclic ring, wherein said ring contains from 3 to 12 carbon atomsin which from 0 to 3 carbon atoms are optionally replaced with a heteromoiety independently selected from N, O, S(O)_(j) wherein j is aninteger from 0 to 2, and —NR¹²—, provided that two O atoms, two S(O)_(j)moieties, an O atom and a S(O)_(j) moiety, an N atom and an S atom, oran N atom and an O atom are not attached directly to each other withinsaid ring, and wherein the carbon atoms of said ring are optionallysubstituted with 1 to 2 R¹¹ groups; each R¹⁰ is independently selectedfrom halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido,hydroxy, C₁-C₆ alkoxy, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷, —NR⁶C(O)NR¹R⁷, —NR⁶C(O)OR⁷,—C(O)NR⁶R⁷, —NR⁵R⁷, —NR⁶OR⁷, —SO₂NR⁶R⁷, —S(O)_(j)(C₁-C₆ alkyl) wherein jis an integer from 0 to 2, —(CR¹R²)_(t)(C₆-C₁₀ aryl), —(CR¹,R²)_(t)(4-10 membered heterocyclic), —(CR¹R²)_(q)C(O)(CR¹R²)_(t)(C₆-C₁₀aryl), —(CR¹R²)_(q)C(O)(CR¹R²)_(t)(4-10 membered heterocyclic),—(CR¹R²)_(t)O(CR¹R²)_(q)(C₆-C₁₀ aryl), —(CR¹R²)_(t)O(CR¹R²)_(q)(4-10membered heterocyclic), —(CR¹R²)_(q)S(O)_(j)(CR¹R²)_(t)(C₆-C₁₀aryl), and—(CR¹R²)_(q)S(O)_(j)(CR¹R²)_(t)(4-10 membered heterocyclic), wherein jis 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R¹⁰groups are optionally substituted with an oxo (═O) moiety, and thealkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoingR¹⁰ groups are optionally substituted with 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl,trifluoromethoxy, azido, —OR⁶, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷,—C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—(CR¹R²)_(t)(C₆-C₁₀ aryl), and —(CR¹R²)_(t) 4-10 membered heterocyclic),wherein t is an integer from 0 to 5; each R¹¹ is independently selectedfrom —R¹², —OR¹, —NR¹R², —NR⁶C(O)R⁷, —NR⁶C(O)NR⁷R¹, —NR⁶C(O)OR⁷, and—NR⁶SO₂NR⁷R¹, or R¹¹ replaces two hydrogen atoms on a carbon to form anoxo (C═O) group; R¹² is R⁶, —C(O)R⁶ or —SO₂R⁶, —C(O)NR⁶R⁷, —SO₂NR⁶R⁷, or—C₂R⁶; R¹³ is —NR¹R¹² or —OR¹² and wherein any of the above-mentionedsubstituents comprising a CH₃ (methyl), CH₂ (methylene), or CH (methine)group which is not attached to a halogeno, SO or SO2 group or to a N, Oor S atom optionally bears on said group a substituent selected fromhydroxy, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and —NR¹R².
 2. A compoundaccording to claim 1 wherein the A moiety is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.
 3. A compoundaccording to claim 1 wherein the A moiety is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.
 4. A compoundaccording to claim 1 wherein the A moiety is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.
 5. A compoundaccording to claim 1 wherein the A moiety is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.
 6. A compoundaccording to claim 1 wherein the A moiety is

wherein the above A moiety bears an R⁴ group as a substituent andoptionally bears 1 to 3 R⁵ groups as substituents.
 7. A compoundaccording to claim 5 wherein R⁴ is —(CR¹R²)_(m)—C≡C—(CR¹R²)_(t)R⁹wherein m is an integer from 0 to 3 and t is an integer from 0 to
 5. 8.A compound according to claim 6 wherein R⁴ is—(CR¹R²)_(m)—C≡C—(CR¹R²)_(t)R⁹ wherein m is an integer from 0 to 3 and tis an integer from 0 to
 5. 9. A compound according to claim 5 wherein R⁴is —(CR¹R²)_(m)—C═C—(CR¹R²)_(t)—R⁹ and m is an integer from 0 to 3 and tis an integer from 0 to
 5. 10. A compound according to claim 6 whereinR⁴ is —(CR¹R²)_(m)—C═C—(CR¹R²)_(t)—R⁹ and m is an integer from 0 to 3and t is an integer from 0 to
 5. 11. A compound according to claim 5wherein R⁴ is —(CR¹R²)_(m)—C═C—(CR¹R²)_(k)R¹³ or—(CR¹R²)_(m)—C═C—(CR¹R²)_(k)R¹³ wherein m is an integer from 0 to 3 andk is an integer from 1 to 3; and q is an integer from 1 to
 6. 12. Acompound according to claim 6 wherein R⁴ is—(CR¹R²)_(m)—C≡C—(CR¹R²)_(k)R¹³ or —(CR¹R²)_(m)—C═C—(CR¹R²)_(k)R¹³wherein m is an integer from 0-3 and k is an integer from 1 to
 3. 13. Acompound according to claim 5 wherein R⁴ is —C═NOR², or —X¹—R¹² whereinX¹ is a divalent group derived from azetidine, oxetane or a C₃-C₄carbocyclic group; or R⁴ is —(CR¹R²)_(t)R⁹, wherein the attachment pointto R⁹ is through a carbon atom of R⁹.
 14. A compound according to claim6 wherein R⁴ is —C═NOR¹², or —X—R¹² wherein X¹ is a divalent groupderived from azetidine, oxetane or a C₃-C₄ carbocyclic group; or R⁴ is—(CR¹R²)_(t)R⁹, wherein the attachment point to R⁹ is through a carbonatom of R⁹.
 15. A compound according to claim 7 wherein R⁸ is selectedfrom —(CR¹R²)_(t)(phenyl), —(CR¹R²)_(t)(pyridyl),—(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²)_(t)(benzimidazolyl), wherein t isan integer from 0 to 5, and each of the foregoing R⁸ groups isoptionally substituted with 1 to 5 R¹⁰ groups.
 16. A compound accordingto claim 8 wherein R⁸ is selected from —(CR¹R²)_(t)(phenyl),—(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²)_(t)(benzimidazolyl), wherein t isan integer from 0 to 5, and each of the foregoing R⁸ groups isoptionally substituted with 1 to 5 R¹⁰ groups.
 17. A compound accordingto claim 9 wherein R⁸ is selected from —(CR¹R²)_(t)(phenyl),—(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²)_(t)(benzimidazolyl), wherein t isan integer from 0 to 5, and each of the foregoing R⁸ groups isoptionally substituted with 1 to 5 R¹⁰ groups.
 18. A compound accordingto claim 10 wherein R⁸ is selected from —(CR¹R²)_(t)(phenyl),—(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²)_(t)(benzimidazolyl), wherein t isan integer from 0 to 5, and each of the foregoing R⁸ groups isoptionally substituted with 1 to 5 R¹⁰ groups.
 19. A compound accordingto claim 11 wherein R⁸ is selected from —(CR¹R²)_(t)(phenyl),—(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²)_(t)(benzimidazolyl), wherein t isan integer from 0 to 5, and each of the foregoing R⁸ groups isoptionally substituted with 1 to 5 R¹⁰ groups.
 20. A compound accordingto claim 12 wherein R⁸ is selected from —(CR¹R²)_(t)(phenyl),—(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²),(benzimidazolyl), wherein t is aninteger from 0 to 5, and each of the foregoing R⁸ groups is optionallysubstituted with 1 to 5 R¹⁰ groups.
 21. A compound according to claim 13wherein R⁸ is selected from —(CR¹R²)_(t)(phenyl), —(CR¹R²)_(t)(pyridyl),—(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyi),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²)_(t)(benzimidazolyl), wherein t isan integer from 0 to 5, and each of the foregoing R⁸ groups isoptionally substituted with 1 to 5 R¹⁰ groups.
 22. A compound accordingto claim 14 wherein R⁸ is selected from —(CR¹R²)_(t)(phenyl),—(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²)_(t)(benzimidazolyl), wherein t isan integer from 0 to 5, and each of the foregoing R⁸ groups isoptionally substituted with 1 to 5 R¹⁰ groups.
 23. A compound accordingto claim 16 wherein the m variable in the R⁴ group is 0, t in the R⁸group is an integer between 0 and 2, and R⁹ is a 4 to 10 memberedheterocyclic group having 1 to 3 hetero moieties as indicated in claim 1wherein said R⁹ is optionally substituted with 1 to 2 R¹¹ groups.
 24. Acompound according to claim 20 wherein R⁴ is—(CR¹R²)_(m)—C≡C—(CR¹R²)_(k)R¹³ wherein m is 0 and k is an integer from1 or
 2. 25. A compound according to claim 22 wherein R⁴ is—(CR¹R²)_(t)R⁹, wherein the attachment point to R⁹ is through a carbonatom of R⁹; t is an integer from 0 to 2, and R⁹ is a 4-10 memberedheterocyclic group having 1 to 3 hetero moieties as indicated in claim 1wherein said R⁹ is optionally substituted with 1 to 2 R¹¹ groups.
 26. Acompound according to claim 1 selected from the group consisting of:Acetic acid3-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-allylester;(1-Benzenesulfonyl-1H-indol-5-yl)-{6-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-quinazolin-4-yl}-amine;(1-Benzenesulfonyl-1H-indol-5-yl)-[6-(3-pyrrolidin-1-yl-prop-1-ynyl)-quinazolin-4-yl]-amine;4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol;(1-Benzenesulfonyl-1H-indol-5-yl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;[6-(4-Amino-tetrahydro-pyran-4-ylethynyl)-quinazolin-4-yl]-(1-benzenesulfonyl-1H-indol-5-yl)-amine;1-Methyl-4-{4-[3-methyl-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylethynyl}-piperidin-4-ol;1-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol;4-{4-[4-(1-Phenyl-ethoxy)-phenylamino]-quinazolin-6-ylethynyl}-tetrahydro-pyran-4-ol;1-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-4,4-dimethyl-pent-1-yn-3-ol;4,4-Dimethyl-1-{4-[4-(1-phenyl-ethoxy)-phenylamino]-quinazolin-6-yl}-pent-1-yn-3-ol;3-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;1-Methyl-3-[4-(4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-pyrrolidin-2-yl-prop-2-yn-1-ol;5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-ylethynyl]-4,4-dimethyl-oxazolidin-2-one;4-Amino-1-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol;4-Amino-1-[4-(3-chloro4-phenoxy-phenylamino)-quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol;3-{2-[4-(3-Methyl4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol;and the pharmaceutically acceptable salts and solvates of the foregoingcompounds.
 27. A compound according to claim 1 selected from the groupconsisting of:(+)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(R)-ylethynyl-quinazolin4-yl)-amine;(−)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(S)-ylethynyl-quinazolin-4-yl)-amine;3-(S)-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylicacid methylamide;3-(S)-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylicacid methylamide;(3-Methyl-4-phenoxy-phenyl)-(6-pyrrolidin-3-ylethynyl-quinazolin-4-yl)-amine;3-[4-(5-Methyl-6-phenoxy-pyridin-3-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;(−)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;(+)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-4-ol;{6-[1-(2-Methoxy-ethyl)-piperidin-3-ylethynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;[4-(2-Fluoro-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;[4-(3-Fluoro-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;(6-Azetidin-3-ylethynyl-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine;3-{4-[4-(2-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;3-{4-[4-(3-Fluoro-phenoxy)-3-methyl-phenyl amino]-qu inazolin-6-ylethynyl}-piperidin-3-ol;4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol;(3-Chloro-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1]octan-3-ol;(3-Chloro-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-3-ol;3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-7-ylethynyl]-piperidin-3-ol;and the pharmaceutically acceptable salts and solvates of the foregoingcompounds.
 28. A compound according to claim 1 selected from the groupconsisting of:N-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;(3-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;4-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazine-1-carboxylicacid methylamide;{6-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)-prop-1-ynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-4-ol;N-{1-Methyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;N-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-methyl-prop-2-ynyl}-acetamide;N-{1,1-Dimethyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-1-methyl-piperidin-4-ol;3-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;3-[4-(3-Bromo-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;3-[4-(4-Benzenesulfonyl-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;3-[4-(4-Cyclohexyloxy-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;2-Methyl-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-2-ol;2-Amino-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-1-ol;3-[4-(3-Methyl-4-phenylsulfanyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;and the pharmaceutically acceptable salts and solvates of the foregoingcompounds.
 29. A compound according to claim 1 selected from the groupconsisting of:3-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;3-[4-(3-Ethynyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;(3-Methyl-4-phenoxy-phenyl)-[6-(1-methyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-amine;(3-Methyl-4-phenoxy-phenyl)-[6-(2-piperidin-3-yl-ethyl)-quinazolin-4-yl]-amine;3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol;3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;3-Oxo-5-(4-pyrrolidin-1-yl-butyl)-1,2,3,5-tetrahydro-benzo[4,5]imidazo[1,2-a]pyridine-4-carboxylicacid benzylamide; and the pharmaceutically acceptable salts and solvatesof the foregoing compounds.
 30. A method for the treatment of abnormalcell growth in a mammal comprising administering to said mammal anamount of a compound of claim 1 that is effective in treating abnormalcell growth. 31 A method according to claim 30 wherein said abnormalcell growth is cancer.
 32. A method according to claim 31 wherein saidcancer is selected from lung cancer, bone cancer, pancreatic cancer,skin cancer, cancer of the head or neck, cutaneous or intraocularmelanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of theanal region, stomach cancer, colon cancer, breast cancer, uterinecancer, carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's Disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, prostatecancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of thebladder, cancer of the kidney or ureter, renal cell carcinoma, carcinomaof the renal pelvis, neoplasms of the central nervous system (CNS),primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, or a combination of one or more of the foregoing cancers.
 33. Amethod for the treatment of abnormal cell growth in a mammal whichcomprises administering to said mammal an amount of a compound of claim1 that is effective in treating abnormal cell growth in combination withan anti-tumor agent selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, radiation, cell cycle inhibitors,enzymes, topoisomerase inhibitors, biological response modifiers,antibodies, cytotoxics, anti-hormones, and anti-androgens.
 34. Apharmaceutical composition for the treatment of abnormal cell growth ina mammal comprising an amount of a compound of claim 1 that is effectivein treating abnormal cell growth, and a pharmaceutically acceptablecarrier.
 35. A method of preparing a compound of claim 1 which compriseseither (a) reacting a compound of the formula 11 or 2 with a compound ofthe formula 3

wherein Z is a leaving group and A, X, R¹, R⁴ and R³ are as definedabove, or (b) reacting a compound of the formula 7 with a compound ofthe formula 3

wherein X, R¹, A, R¹ and R³ are as defined above and Z¹ is an activatinggroup, to provide an intermediate of the formula 5

wherein Z¹, X, R¹, A, and R³ are as defined above and Z¹ is converted toan R⁴ group which optionally may be converted to another R⁴ group.